Processes useful for the preparation of 1-[3-(4-bromo-2-methyl-2h-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea and crystalline forms related thereto

ABSTRACT

The present invention is directed to processes and intermediates useful for the preparation of 1-[3-(4-bromo-2-N methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea (Compound I), crystalline forms and solvate forms thereof; and compositions comprising 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea, crystalline forms and solvate forms thereof prepared by processes as described herein.

FIELD OF THE INVENTION

The present invention is directed to processes and intermediates usefulfor the preparation of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea(Compound I), crystalline forms and solvate forms thereof; andcompositions comprising1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea,crystalline forms and solvate forms thereof prepared by processes asdescribed herein.

BACKGROUND OF THE INVENTION

The compound,1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea(Compound I, shown below), which is described in PCT ApplicationPCT/US2004/023488 and incorporated herein by reference in its entirety,belongs to a class of serotonin 5-HT_(2A)-receptor modulators that areuseful in the treatment of serotonin 5-HT_(2A)-receptor associateddiseases and disorders.

1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea(Compound I)

Certain synthetic processes for preparing1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureahave been described in PCT Applications PCT/US2004/023880 andPCT/US2006/002721, both of which are incorporated herein by reference intheir entirety.

PCT Application PCT/US2004/023880 discloses processes that prepare1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureafrom 3-(4-bromo-2-methyl-2H-methyl-3-yl)-4-methoxy-phenylamine and2,4-difluorophenyl-isocyanate in the presence of toluene (Example 5, PCTApplication PCT/US2004/023880) with an impurity of 0.9 mole % identifiedas the desbromo of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureaand an overall purity of 98.2% purity by HPLC. While the solid stateproperties for1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureawere not characterized, it was found in a subsequent experiment that thetoluene process as described in Example 5 (PCT ApplicationPCT/US2004/023880) was observed to be a mixture of at least Form I andForm II.

PCT Application PCT/US2006/002721 discloses processes that prepare1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureafrom 3-(4-bromo-2-methyl-2H-methyl-3-yl)-4-methoxy-phenylamine and2,4-difluorophenyl-isocyanate in the presence of an alcoholic solvent,such as methanol and n-propanol (Examples 1-5, PCT ApplicationPCT/US2006/002721) to give substantially Form II.

Although Form II is considered the more thermodynamically stablepolymorph, Form I was identified as the desirable crystalline form basedon, inter alia, improved pharmacokinetic characteristics. Accordingly,there exists a need for efficient synthetic procedures for preparingForm I of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureathat are economically effective, provide batch-to-batch consistency, aswell as the preparation of Form I that is substantially pure and/or freeof harmful contaminants in bulk quantity. The synthetic procedures andintermediates for1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea(Compound I), as described herein, meet one or more of these and otherneeds.

SUMMARY OF THE INVENTION

The present invention provides, inter alia, processes and intermediatesfor preparing1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea(Compound I), crystalline forms and solvate forms thereof.

One aspect of the present invention relates to processes for preparingForm I of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureacomprising the step of:

converting an acetonitrile solvate of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureato provide Form I of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea.

One aspect of the present invention relates to processes for preparingan acetonitrile solvate of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureacomprising the steps of:

a) reacting 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylaminewith 2,4-difluorophenyl-isocyanate in the presence of acetonitrile toform a reaction mixture comprising1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea;and

b) crystallizing1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureafrom the reaction mixture to form the acetonitrile solvate of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea.

One aspect of the present invention relates to processes for preparing3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine, the processcomprising:

reactingN-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-acetamide withan inorganic base in the presence of a mixture of an aromatic solventand a C₁-C₆ alkanol to form3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine.

One aspect of the present invention relates to processes for preparing1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureacomprising the steps of:

a) reacting N-[4-methoxy-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-acetamidewith a brominating agent in the presence of a brominating solvent toformN-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-acetamide;

b) reactingN-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-acetamide withan inorganic base in the presence of a mixture of an aromatic solventand a C₁-C₆ alkanol to form3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine; and

c) reacting 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylaminewith 2,4-difluorophenyl-isocyanate in the presence of a urea-formingsolvent to form1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea.

One aspect of the present invention relates to processes for preparingForm I of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea,the process comprising:

a) dissolving1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureain tetrahydrofuran to form a solution;

b) adding an aliphatic solvent to the solution to form a mixturecomprising a first solvate of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea;

c) isolating the first solvate of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureafrom the mixture to provide an isolated first solvate of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea;

d) washing the isolated first solvate of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureawith acetonitrile to form a second solvate of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea;and

e) converting the second solvate to provide Form I of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea.

One aspect of the present invention relates to compositions comprisingForm I of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureaprepared according to any of the processes described herein, wherein thecomposition comprises less than 0.9 mole % of1-(2,4-difluorophenyl)-3-(4-methoxy-3-(1-methyl-1H-pyrazol-5-yl)phenyl)urea.

One aspect of the present invention relates to processes for preparingpharmaceutical compositions comprising admixing:

a composition comprising Form I of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureaprepared according to any of the processes described herein, whereinsaid composition comprises less than 0.9 mole % of1-(2,4-difluorophenyl)-3-(4-methoxy-3-(1-methyl-1H-pyrazol-5-yl)phenyl)urea;and

a pharmaceutically acceptable carrier.

One aspect of the present invention relates to an acetonitrile solvateof1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea.In some embodiments, the acetonitrile solvate has a molecular ratio ofacetonitrile to1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureaof about 1:2.

One aspect of the present invention relates to an acetonitrile solvateof1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea.In some embodiments; the acetonitrile solvate has a molecular ratio ofacetonitrile to1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureaof about 1:2.

One aspect of the present invention relates to compositions comprisingan acetonitrile solvate of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureaprepared according to any of the processes described herein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts APD125 plasma exposure in monkeys after oraladministration of wet-granulation tablets (composition: 30 mg APD125Form I or Form II in a ratio of 1:8 to PVP) or SGCs (composition: 40 mgAPD125 in Cremophor®:Labrasol® [1:1], Dose Adjusted to 30 mg).

FIG. 2 depicts APD125 plasma exposure in monkeys after oraladministration of wet-granulation tablets (composition: 10 mg APD125Form I:PVP [1:8]) or SGC (composition: 10 mg APD125 inCremophor®:Labrasol® [1:1]).

FIG. 3: depicts monkey PK exposure results for 10-mg and 30-mg APD125Form I wet-granulation tablets versus 10-mg and 40-mg SGCs.

FIG. 4 depicts the 1-month and 3-month PXRD results for thewet-granulation Form I based tablet. The PXRD patterns show that thesamples substantially comprise Form I at both time points.

FIG. 5 depicts the 1-month and 3-month PXRD results for thewet-granulation Form II based tablet. The PXRD patterns show that thesamples substantially comprise Form II at both time points.

FIG. 6 depicts PXRD patterns for micronized APD125 Form I, before andafter grinding with a mortar and pestle for 1 minute, 5 minutes and 10minutes. The PXRD patterns show that the samples all substantiallycomprise Form I.

FIG. 7 depicts PXRD patterns of APD125 Form I compressed at 2 kp, 5 kpand 10 kp compared with uncompressed Form I. The PXRD patterns show thatthe samples all substantially comprise Form I.

FIG. 8 depicts a PXRD pattern of an aqueous 0.5% w/w methyl cellulosesolution of Form I at room temperature and 40° C. after 16 days. ThePXRD pattern shows that the sample has substantially converted to FormII.

FIG. 9 depicts PXRD patterns of a Form I paste in water alone at roomtemperature and 40° C. after 24 h. The PXRD pattern shows that thesample has substantially converted to Form II.

FIG. 10 depicts PXRD patterns for the wet-granulation Form I tabletblend post-mixing without water at t=0, and with 50% w/w water at t=0and 24-h storage at room temperature and 40° C. The PXRD patterns showthat each sample substantially comprises Form I.

FIG. 11 depicts PXRD patterns for the Form I wet-granulation tabletblend post-mixing with 50% w/w water at t=0, 24-h, 7-days and 21-daysstorage at room temperature. The PXRD patterns show that at t=0, 24-hand 7-days the samples substantially comprise Form I, and at t=21 daysthe sample has substantially converted to Form II.

FIG. 12 depicts PXRD patterns for PVP-based direct-compression Form Itablets, containing 0% w/w, 2% w/w, 5% w/w and 8% w/w methyl celluloseand a coPVP-based direct-compression Form I tablet, containing 5% w/wmethyl cellulose, post-mixing with 50% w/w water at t=0. The PXRDpatterns show that each sample substantially comprises Form I.

FIG. 13 depicts PXRD patterns for PVP-based direct-compression Form Itablets, containing 0% w/w, 2% w/w, 5% w/w and 8% w/w methyl cellulose,and a coPVP-based direct-compression tablet, containing 5% w/w methylcellulose, post-mixing with 50% w/w water after 24 h at 40° C. The PXRDpatterns show that the sample containing 0% methyl cellulose hassubstantially converted to Form II and all other samples substantiallycomprise Form I.

FIG. 14 depicts PXRD patterns for PVP-based direct-compression Form Itablets, containing 0% w/w, 2% w/w, 5% w/w and 8% w/w methyl cellulose,and a coPVP-based direct-compression Form I tablet, containing 5% w/wmethyl cellulose, post-mixing with 50% w/w water after 1 week at 40° C.The PXRD patterns show that the sample containing 2% methyl cellulosehas substantially converted to Form II and all other samplessubstantially comprise Form I.

FIG. 15 depicts PXRD patterns for PVP-based direct-compression Form Itablets, containing 5% w/w and 8% w/w methyl cellulose, and acoPVP-based direct-compression From I tablet, containing 5% w/w methylcellulose, post-mixing with 50% w/w water after 1 month at 40° C. ThePXRD patterns show that the sample containing PVP and 5% methylcellulose substantially comprises Form I, the sample containing PVP and8% methyl cellulose has partially converted to Form II, and the samplecontaining coPVP has substantially converted to Form II. Note that thetablet PXRD data acquisition scan window was reduced to two smallerregions of 6.5° to 8° 2θ and 11.8° to 13.3° 2θ to reduce the overallsample analysis time, while maintaining the ability to discriminate FormI from Form II.

FIG. 16 depicts the effect of APD125/Pvp ratio on the APD125 plasmaexposure in monkeys after oral administration of 10-mgdirect-compression (dry) tablets.

FIG. 17 depicts the effect of PVP and coPVP on the APD125 plasmaexposure in monkeys after oral administration of 10-mgdirect-compression (dry) tablets, containing either APD125:PVP (1:8) orAPD125:coPVP (1:8).

FIG. 18 depicts APD125 plasma exposure in monkeys after oraladministration of direct-compression tablets (composition: 40 mg APD125Form I:PVP [1:8], containing 2% w/w methyl cellulose) or SGCs(composition: 40 mg APD125 in Cremophor®:Labrasol® [1:1]).

FIG. 19 depicts a hygroscopicity plot for Plasdone™ S-630 (coPVP)copolymer versus Plasdone™ K-29/32 (PVP) homopolymer.

FIG. 20 depicts APD125 plasma exposure in monkeys after oraladministration of direct-compression tablets (10 mg) containing eitherAPD125:PVP (1:8) or APD125:coPVP (1:8).

FIG. 21 depicts a powder X-ray diffraction (PXRD) pattern for Form I of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea(Compound I), which was recorded using a PANalytical X'Pert Plus PowderX-Ray Diffractometer in the theta/theta geometry; scanning angles5.0°-40.0° 2θ.

FIG. 22 depicts a differential scanning calorimetry (DSC) thermogram forForm I of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea(Compound I), which was recorded using a TA Instruments DSC Q1000; at10° C./min.

FIG. 23 depicts an FT Raman spectrum for Form I of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea(Compound I), which was recorded using a ThermoFisher NXR6700 FT-RamanSpectrometer (EQ1874) using the FT-Raman Micro-Stage Accessory.

FIG. 24 depicts a thermogravimetric analysis (TGA) thermogram for Form Iof1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea(Compound I), which was recorded using a TA Instruments TGA Q500 in anitrogen atmosphere. The percent change in weight as a function oftemperature was recorded.

FIG. 25 depicts a pictorial representation of the hemi-acetonitrilesolvate of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea(Form IV) as generated by Mercury v. 1.4.2 (build 2) based onsingle-crystal X-ray diffraction analysis.

FIG. 26 depicts the comparison of calculated PXRD pattern ofhemi-acetonitrile solvate of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea(Form IV), based upon single-crystal X-diffraction results obtained atca. 150° K versus bulk Form IV isolated from acetonitrile and analyzedat ca. 298° K.

FIG. 27 depicts a powder X-ray diffraction (PXRD) pattern for aAcetonitrile Solvate of1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea,which was recorded using a PANalytical X'Pert Plus Powder X-RayDiffractometer in the 20 geometry; scanning angles 5.0°-40.0° 2θ.

FIG. 28 depicts the transient X-ray powder diffraction patterns observedas Form IV of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureaconverts into Form I, which was recorded using a PANalytical X'Pert PlusPowder X-Ray Diffractometer in the 20 geometry; scanning angles5.0°-40.0° 2θ.

FIG. 29 depicts a powder X-ray diffraction (PXRD) pattern for atetrahydrofuran solvate of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea,which was recorded using a PANalytical X'Pert Plus Powder X-RayDiffractometer in the 20 geometry; scanning angles 5.0°-40.0° 2θ.

FIG. 30 depicts a powder X-ray diffraction (PXRD) pattern for a HeptaneSolvate of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea,which was recorded using a PANalytical X'Pert Plus Powder X-RayDiffractometer in the theta/theta geometry; scanning angles 5.0°-40.0°2θ.

FIG. 31 depicts a powder X-ray diffraction (PXRD) pattern for Form II of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea(Compound I), which was recorded using a PANalytical X'Pert Plus PowderX-Ray Diffractometer in the theta/theta geometry; scanning angles5.0°-40.0° 2θ.

DETAILED DESCRIPTION OF THE INVENTION

1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea(Compound I) is a potent inverse agonist of the serotonin5-HT_(2A)-receptor and as such is useful for the treatment of serotonin5-HT_(2A)-receptor associated diseases and disorders, for example,increasing slow wave sleep, improving sleep consolidation, improvingsleep maintenance and improving sleep quality, and for treating insomniaand related sleep disorders, dyssomnias, parasomnias and nonrestorativesleep and the like; and treating platelet aggregation, coronary arterydisease, myocardial infarction, transient ischemic attack, angina,stroke, atrial fibrillation, thrombosis, asthma or symptoms thereof,agitation or symptoms thereof, behavioral disorders, drug inducedpsychosis, excitative psychosis, Gilles de la Tourette's syndrome, manicdisorder, organic or NOS psychosis, psychotic disorders, psychosis,acute schizophrenia, chronic schizophrenia, NOS schizophrenia andrelated disorders, diabetic-related disorders and progressive multifocalleukoencephalopathy and the like.

Definitions

The term “C₅-C₁₀ alkane” as used herein refers to a straight chain orbranched chain alkane with 5 to 10 carbon atoms. Examples includehexane, heptane and the like.

The term “C₁-C₆ alkanol” as used herein refers to a compound of formulaC₁-C₆ alkyl-OH where the alkyl group has 1 to 6 carbon atoms. Examplesinclude methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanoland the like.

The term “aromatic solvent” as used herein refers to a solvent or anisomeric mixture of solvents that contains one aromatic ring and isoptionally substituted with 1, 2 or 3 substituents provided that thesolvent is a liquid at ambient temperature. Examples include benzene,toluene, o-xylene, m-xylene, p-xylene, xylenes and the like.

The term “C₅-C₈ cycloalkane” as used herein refers to a cyclic alkanewith 5 to 8 carbon atoms. Examples include cyclohexane, cycloheptane andthe like.

The term “inorganic base” as used herein refers to a base selected froman alkali metal hydroxide and alkaline earth hydroxide. Examples includelithium hydroxide, sodium hydroxide, potassium hydroxide and the like.

The term “ICH” as used herein refers to The International Conference onHarmonization of Technical Requirements for Registration ofPharmaceuticals for Human Use (ICH).

The terms “5-HT_(2A) serotonin receptor-related disorder” and “5-HT_(2A)serotonin receptor-related disease” as used herein respectively refer toa disorder or disease in an individual, which may be prevented,inhibited, ameliorated, treated or cured by modulation (e.g. agonsim,antagonism or inverse agonism) of the 5HT_(2A) serotonin receptor, forexample, by administering to the individual in need thereof atherapeutically effective amount of a pharmaceutical composition of thepresent invention comprising a 5HT_(2A) serotonin receptor modulator.

The term “in need of treatment” as used herein refers to a judgment madeby a caregiver (e.g. physician, nurse, nurse practitioner, etc. in thecase of humans; veterinarian in the case of animals, including non-humanmammals) that an individual or animal requires or will benefit fromtreatment. This judgment is made based on a variety of factors that arein the realm of a caregiver's expertise, but that includes the knowledgethat the individual or animal is ill, or will become ill, as the resultof a disease, condition or disorder that is treatable by the compoundsof the invention. Accordingly, the compounds of the invention can beused in a protective or preventive manner; or compounds of the inventioncan be used to alleviate, inhibit or ameliorate the disease, conditionor disorder.

The term “individual” as used herein refers to any animal, includingmammals, preferably mice, rats, other rodents, rabbits, dogs, cats,swine, cattle, sheep, horses, or primates, and most preferably humans.

The term “inverse agonists” as used herein refers to moieties that bindthe endogenous form of the receptor or to the constitutively activatedform of the receptor, and which inhibit the baseline intracellularresponse initiated by the active form of the receptor below the normalbase level of activity which is observed in the absence of agonists orpartial agonists, or decrease GTP binding to membranes. Preferably, thebaseline intracellular response is inhibited in the presence of theinverse agonist by at least 30%, more preferably by at least 50%, andmost preferably by at least 75%, as compared with the baseline responsein the absence of the inverse agonist.

The term “therapeutically effective amount” as used herein refers to theamount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue, system, animal, individualor human that is being sought by a researcher, veterinarian, medicaldoctor or other clinician, which includes one or more of the following:

(1) Preventing the disease; for example, preventing a disease, conditionor disorder in an individual that may be predisposed to the disease,condition or disorder but does not yet experience or display thepathology or symptomatology of the disease;

(2) Inhibiting the disease; for example, inhibiting a disease, conditionor disorder in an individual that is experiencing or displaying thepathology or symptomatology of the disease, condition or disorder (i.e.,arresting further development of the pathology and/or symptomatology);and

(3) Ameliorating the disease; for example, ameliorating a disease,condition or disorder in an individual that is experiencing ordisplaying the pathology or symptomatology of the disease, condition ordisorder (i.e., reversing the pathology and/or symptomatology).

The term “sleep maintenance” as used herein refers to the ability tosleep without persistent interruptions or extended periods ofwakefulness. Sleep Maintenance Insomnia is a disturbance in maintainingsleep after sleep onset is achieved. It is characterized by persistentlyinterrupted sleep without difficulty falling asleep, andsleep-continuity disturbance. Parameters used for measuring sleepmaintenance include but are not limited to, wake time after sleep onset(WASO) and number of awakenings (NAW).

The term “sleep quality” as used herein refers to both the subjectiveassessment given by an individual of how restorative and undisturbedsleep has been (via a standardized questionnaire) and to a series ofobjective measures derived from polysomnography. Examples ofstandardized sleep questionnaires, include but are not limited to thePittsburgh Sleep Quality Index (Buysse et al., Psychiatry Research(1989), 28(2), 193-213). Examples of objective measures of sleep qualityinclude, but are not limited to, the amount and depth of nonREM sleep,the amount of REM sleep and the temporal organization of nonREM and REMstages. Subjective and objective measures of sleep quality are notnecessarily concordant.

The term “nonrestorative sleep” as used herein refers to a disordercharacterized by the subjective assessment given by an individual thatsleep is restless, light, or of poor quality even though the durationmay appear normal. NRS is associated with other symptoms including, butnot limited to, excessive daytime sleepiness, mood swings and cognitiveimpairments.

The term “coPVP” as used herein refers to a vinylpyrrolidone-vinylacetate copolymer, CAS registry number 25086-89-9. The term is usedinterchangeably with the terms copolyvidonum Plasdone™, copovidone andcopolyvidone. coPVP has following structural formula:

In some embodiments coPVP is a copolymer of 1-vinyl-2-pyrrolidone andvinyl acetate in a ratio of 6:4 by mass, wherein n≈1.2 m. Examples ofcoPVP include but are not limited to Kollidon™ VA 64, Plasdone™ S-630and the like.

The term “cps” as used herein is intended to refer to the unit ofdynamic viscosity known as the centipoise (cP). 1 cP=1 millipascalsecond.

The term “DFA” as used herein refers to 2,4-difluoroaniline, CASregistry number 367-25-9, which represented by the following formula:

The term “HIDPE” as used herein refers to high-density polyethylene.

The term “MCC” as used herein refers to microcrystalline cellulose, CASregistry number 9004-34-6. The term is used interchangeably with theterms cellulose gel, crystalline cellulose and E460. MCC has thefollowing structural formula:

wherein n≈220.

Examples of MCC include, but are not limited to, Avicel™ PH, Avicel™ PH102, Celex™, Celphere™, Ceolus™ KG, Emcocel™, Ethispheres™, Fibrocel™,Pharmacel™, Tabulose™ and Vivapur™.

The term “PIC” as used herein refers to powder in capsule.

The term “Poloxamer” as used herein refers to a class of pharmaceuticalexcipients comprising or consisting essentially of either a singlecompound or a mixture of compounds prepared from synthetic blockcopolymers of ethylene oxide and propylene oxide. In some embodiments,an excipient in this class comprises or consists essentially of a singlecompound or a mixture of compounds of the following formula:

wherein “b” at each occurrence is independently an integer between 1 to102; “c” is an integer between 1 and 57; b+c+b is 3 to 327; and theaverage molecule weight of the poloxamer is about 17500 or less.Poloxamers are known or can be prepared by methods in the art. A numberof poloxamers are commercially available. Representative examples of aPoloxamer include, but are not limited to, Poloxamer 124 (Pluronic®L44NF), Poloxamer 188 (Pluronic® F68NF), Poloxamer 237 (Pluronic®F87NF), Poloxamer 338 (Pluronic® F108NF), Poloxamer 407 (Pluronic®F127NF) and the like.

The term “PVA” as used herein refers to polyvinyl alcohol, CAS registrynumber 9002-89-5. The term is used interchangeably with the term vinylalcohol polymer. PVA has the following structural formula:

wherein n lies between 500 and 5000, equivalent to a molecular weightrange of approximately 20,000 to 200,000. In some embodiments PVA ishigh viscosity with a molecular weight≈200,000. In some embodiments PVAis medium viscosity with a molecular weight≈130,000. In some embodimentsPVA is medium viscosity with a molecular weight≈20,000. Examples of PVAinclude but are not limited to Airvol™, Elvanol™ and Gohsenol™

The term “PVP” as used herein refers to polyvinylpyrrolidone. The termis used interchangeably with the terms, E1201, povidone, povidonum,poly[1-(2-oxo-1-pyrrolidinyl)ethylene, polyvidone and1-vinyl-2-pyrrolidinone polymer. PVP has the following structuralformula:

wherein the molecular weight is from about 2500 to about 3,000,000.Examples of PVP include, but are not limited to, Kollidon™, Kollidon™ VA64, Plasdone™, Plasdone™ K-29/32 and Kollidon™ 30.

The term “% RSD” as used herein refers to the relative standarddeviation, which is the absolute value of the coefficient of variationexpressed as a percentage. The term is widely used in analyticalchemistry to express the precision of an assay:

(standard deviation of array X)×100/(average of array X)=relativestandard deviation.

The term “SGC” as used herein refers to a soft gelatin capsule.

The term “SLS” as used herein refers to sodium lauryl sulfate, which hasthe following structural formula:

The term “xCMC” as used herein refers to croscarmellose sodium, CASRegistry Number 74811-65-7. The term is used interchangeably with theterms carmellosum natricum conexum, crosslinked carboxymethyl cellulosesodium and modified cellulose gum. xCMC is a crosslinked polymer ofcarboxymethyl cellulose sodium. Carboxymethyl cellulose sodium has thefollowing structural formula:

Examples of xCMC include, but are not limited to, Ac-Di-Sol™, Explocel™,Nymcel™ ZSX, Pharmacel™ XL, Primellose™, Solutab™ and Vivasol™.

The term “xPVP” as used herein refers to crosslinked povidone, CASregistry number 9003-39-8, wherein povidone has the same definition asdescribed herein. The term is used interchangeably with the termscrospovidone, crospovidonum, E1202, polyvinylpolypyrrolidone, PVPP,1-vinyl-2-pyrrolidinone and 1-ethenyl-2-pyrrolidinone homopolymer.Examples of xPVP include, but are not limited to, PolyPlasdone™ XL,PolyPlasdone™ XL-10, Kollidon™ CL and Kollidon™ CL-M.

It is appreciated that certain features of the invention, which are, forclarity, described in the context of separate embodiments, may also beprovided in combination in a single embodiment. Conversely, variousfeatures of the invention, which are, for brevity, described in thecontext of a single embodiment, may also be provided separately or inany suitable subcombination.

All combinations of the embodiments pertaining to the aspects describedherein are specifically embraced by the present invention just as ifeach and every combination was individually explicitly recited, to theextent that such combinations embrace possible aspects. In addition, allsubcombinations of the embodiments contained within the aspectsdescribed herein, as well as all subcombinations of the embodimentscontained within all other aspects described herein, are alsospecifically embraced by the present invention just as if each and everysubcombination of all embodiments are explicitly recited herein.

CERTAIN ASPECTS OF THE PRESENT INVENTION 1. Form I of1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea(Compound I), Processes and Compositions related thereto

One aspect of the present invention is directed to the preparation ofForm I of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea(Compound I) and compositions thereof. Form I can be identified by itsunique solid state signature with respect to, for example, differentialscanning calorimetry (DSC), powder X-ray diffraction (PXRD), IR Ramanspectroscopy and other solid state methods. Further characterizationwith respect to water or solvent content of the crystalline form can begauged by any of the following methods for example, thermogravimetricanalysis (TGA), DSC and the like. For DSC, it is known that thetemperatures observed for thermal events will depend upon the rate oftemperature change as well as sample preparation technique and theparticular instrument employed. Thus, the values reported hereinrelating to DSC thermograms can vary by plus or minus about 4° C. Thevalues reported herein relating to DSC thermograms can also vary by plusor minus about 20 joules per gram. In samples contaminated with Form IIof1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureathe values reported herein relating to DSC thermograms can vary by plusor minus >20 joules per gram. For PXRD, the relative intensities of thepeaks can vary, depending upon the sample preparation technique, thesample mounting procedure and the particular instrument employed.Moreover, instrument variation and other factors can often affect the 2θvalues. Therefore, the peak assignments of diffraction patterns can varyby plus or minus about 0.2° 2θ. For TGA, the features reported hereincan vary by about ±5° C. The TGA features reported herein can also varyby about ±2% weight change due to, for example, sample variation.Further characterization with respect to hygroscopicity of thecrystalline form can be gauged by, for example, dynamic vapor sorption(DVS). The DVS features reported herein can vary by about ±5% relativehumidity. The DVS features reported herein can also vary and by about±5% weight change.

The physical properties of crystalline Form I of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea(Compound I) are summarized in Table A below.

TABLE A Characterization of Form I of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea (Compound I) PXRDFIG. 21: Peaks of about 17% or greater relative intensity at 5.6°, 7.4°,11.2°, 21.1° and 25.0° 2θ DSC FIG. 22: an endotherm with an extrapolatedonset temperature of about 170° C., an associated heat flow of about 64joules per gram and a peak temperature of about 172° C. FT FIG. 23:Peaks at 3086, 2955, 2840, 1656, 1622, 1605, 1572, RAMAN 1534, 1004,1004, 964, 911, 759, 751, 732, 723, 673, 505, 390, 335 and 315 cm⁻¹ TGAFIG. 24: negligible weight loss below about 150° C.

The negligible weight loss observed in the TGA data suggests that Form Iof1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea(Compound I) is an anhydrous, non-solvated crystalline form. The DSCthermogram further reveals a melting endotherm with an onset at about170° C.

A further aspect of the present invention is directed to compositionscomprising Form I of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureaand less than 0.9 mole % of1-(2,4-difluorophenyl)-3-(4-methoxy-3-(1-methyl-1H-pyrazol-5-yl)phenyl)urea.

One aspect of the present invention is directed to compositionscomprising Form I of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea,wherein the compositions comprise less than 0.9 mole % of1-(2,4-difluorophenyl)-3-(4-methoxy-3-(1-methyl-1H-pyrazol-5-yl)phenyl)urea.In some embodiments, Form I of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureaconstitutes at least about 0.1% by weight of the composition. In someembodiments, Form I of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureaconstitutes at least about 1% by weight of the composition. In someembodiments, Form I of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureaconstitutes at least about 5% by weight of the composition. In someembodiments, Form I of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureaconstitutes at least about 10% by weight of the composition. In someembodiments, Form I of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureaconstitutes at least about 15% by weight of the composition. In someembodiments, Form I of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureaconstitutes at least about 20% by weight of the composition. In someembodiments, Form I of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureaconstitutes at least about 30% by weight of the composition. In someembodiments, Form I of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureaconstitutes at least about 40% by weight of the composition. In someembodiments, Form I of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureaconstitutes at least about 50% by weight of the composition. In someembodiments, Form I of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureaconstitutes at least about 60% by weight of the composition. In someembodiments, Form I of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureaconstitutes at least about 70% by weight of the composition. In someembodiments, Form I of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureaconstitutes at least about 80% by weight of the composition. In someembodiments, Form I of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureaconstitutes at least about 90% by weight of the composition. In someembodiments, Form I of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureaconstitutes at least about 95% by weight of the composition.

One aspect of the present invention is directed to compositionscomprising Form I of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureaand less than 0.9 mole % of1-(2,4-difluorophenyl)-3-(4-methoxy-3-(1-methyl-1H-pyrazol-5-yl)phenyl)ureaand further comprising a pharmaceutically acceptable carrier. In someembodiments, the composition is formulated for oral administration. Insome embodiments, the composition is in the form of a pill, capsule ortablet.

2. Converting an acetonitrile solvate of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureato Form I of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea(Compound I)

One aspect of the present invention relates to processes for preparingForm I of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureacomprising the step of:

converting an acetonitrile solvate of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureato provide Form I of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea.

In some embodiments, the acetonitrile solvate of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureahas a molecular ratio of acetonitrile to1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureaof about 1:2 (i.e., hemi-acetonitrile solvate of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea).

A single-crystal X-ray diffraction analysis demonstrated theacetonitrile solvate to exist as a hemi-acetonitrile solvate, containinga theoretical acetonitrile content of 4.75% w/w, having the molecularformula C₁₈H₁₅BrF₂N₂O₂.0.5(CH₃CN), referred herein as Form IV andhemi-acetonitrile solvate of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea.A pictorial representation of the hemi-acetonitrile solvate as generatedby is Mercury v. 1.4.2 (build 2) is shown in FIG. 25. A calculated X-raypowder diffraction pattern of Form IV, derived from the single-crystalresults, is provided in FIG. 26, which is overlaid with anexperimentally obtained X-ray powder diffraction pattern of bulkacetonitrile solvate Form IV isolated from acetonitrile. FIG. 27 showsthe experimentally obtained X-ray powder diffraction pattern without thecalculated PXRD.

Upon solvent content reduction, by evaporation and/or heating, Form IVwill convert to Form I, exhibiting a range of X-ray powder diffractionpatterns (FIG. 28) potentially intermediate in appearance between FormsIV and I and/or having the appearance of binary mixtures of Forms IV andI until the sample in question has fully converted to Form I. Once FormIV is isolated from acetonitrile the conversion from Form IV to Form Ican occur within minutes to weeks, depending upon storage or dryingconditions. Since the conversion to Form I can potentially occur quitequickly upon isolation from acetonitrile at room temperature, X-raypowder diffraction patterns obtained during the conversion process canbe complicated by potential Form IV to Form I conversion duringacquisition of a single X-ray powder diffraction pattern. Onceconversion of Form IV to Form I is complete, a well-defined andcharacteristic X-ray powder diffraction pattern of Form I is observed.

The conversion of the acetonitrile solvate of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea(for example, Form IV) to Form I of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureacan be conducted under a variety of reduced pressures and temperatures.

In some embodiments, the converting an acetonitrile solvate of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureais conducted under reduced pressure. In some embodiments, the convertingan acetonitrile solvate of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureais conducted at a reduced pressure of about 100 mm Hg or less. In someembodiments, the converting an acetonitrile solvate of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureais conducted at a reduced pressure of about 35 mm Hg or less. In someembodiments, the converting an acetonitrile solvate of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureais conducted at a reduced pressure of about 10 mm Hg or less. In someembodiments, the converting an acetonitrile solvate of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureais conducted at a reduced pressure of about 5 mm Hg or less.

If the acetonitrile solvate of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea(Form IV) is left in acetonitrile or if during post-isolation fromacetonitrile the residual solvent content is too great then there is arisk that Form IV will convert to Form II. Therefore, as the solventcontent is decreased the risk of Form IV converting to Form II isreduced. The undesirable conversion of Form IV to Form II was found tobe temperature dependent and as a result, by controlling the temperaturethe conversion of Form IV to Form II could be minimized. Accordingly,the conversion of Form IV to Form I of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureacan be conducted at a first temperature and then at a second temperatureoptionally under reduced pressure.

In some embodiments, converting the acetonitrile solvate of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureais conducted during at least two time periods, wherein the conversion isconducted at a first temperature during a first time period and whereinthe conversion is conducted at a second temperature during a second timeperiod, and wherein the first temperature is not equivalent to thesecond temperature.

In some embodiments, the second temperature is higher than the firsttemperature.

In some embodiments, the first temperature is at about 0° C. to about45° C. In some embodiments, the first temperature is at about 15° C. toabout 40° C. In some embodiments, the first temperature is at about 20°C. to about 30° C.

In some embodiments, the second temperature is about 45° C. to about 90°C. In some embodiments, the second temperature is about 60° C. to about80° C. In some embodiments, the second temperature is about 65° C. toabout 75° C.

In some embodiments, the first temperature is at about 20° C. to about30° C. and the second temperature is about 65° C. to about 75° C.

The first temperature can be maintained until the solvent content issufficiently reduced to minimize the conversion to Form II. Loss ondrying (LOD) is one method for determining the solvent content presentin the bulk material. This is achieved by obtaining representativesamples of the bulk material at various time points and determining theLOD. The LOD for each sample is expressed as the percentage of volatileslost during the drying of the sample and indicates the percent of thevolatiles that remain in the bulk material at the specific time thesample was obtained. Once the suitable LOD level or solvent content isachieved then the second temperature is initiated. A variety ofinstruments can be used for LOD determinations; one such instrument is amoisture analyzer by Denver Instruments (Model IR-200 or equivalentmodel).

In some embodiments, the first temperature is maintained until the LODis about 35%, about 30%, about 25%, about 20%, about 15%, about 10%,about 5% or less for a representative sample of the bulk materialobtained from any of the process as described herein before initiatingthe second temperature, optionally this process can be conducted underreduced pressure.

Loss on drying is a method that can be used to determine the amount ofvolatiles when conducting large scale processes, other suitable methodscan also be used, such as, ¹H NMR, gas chromatography (such as,head-space GC), thermogravimetric analysis (TGA) and the like.

In some embodiments the process further comprises the step ofmaintaining the first temperature until a loss on drying (LOD) for arepresentative sample from the process is at a level of about 30% orless. In some embodiments the process further comprises the step ofmaintaining the first temperature until a loss on drying (LOD) for arepresentative sample from the process is at a level of about 20% orless. In some embodiments the process further comprises the step ofmaintaining the first temperature until a loss on drying (LOD) for arepresentative sample from the process is at a level of about 15% orless. In some embodiments the process further comprises the step ofmaintaining the first temperature until a loss on drying (LOD) for arepresentative sample from the process is at a level of about 10% orless.

In some embodiments, converting the acetonitrile solvate of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureais conducted at a first temperature of about 0° C. to about 45° C. untila loss on drying (LOD) for a representative sample from the process isat a level of about 30% or less and thereafter raising to a secondtemperature of about 45° C. to about 90° C. In some embodiments,converting the acetonitrile solvate of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureais conducted at a first temperature of about 15° C. to about 40° C.until a loss on drying (LOD) for a representative sample from theprocess is at a level of about 20% or less and thereafter raising to asecond temperature about 60° C. to about 80° C. In some embodiments,converting the acetonitrile solvate of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureais conducted at a first temperature of about 20° C. to about 30° C.until a loss on drying (LOD) for a representative sample from theprocess is at a level of about 15% or less and thereafter raising to asecond temperature of about 60° C. to about 80° C. In some embodiments,converting the acetonitrile solvate of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureais conducted at a first temperature of about 20° C. to about 30° C.until a loss on drying (LOD) for a representative sample from theprocess is at a level of about 10% or less and thereafter raising to asecond temperature of about 65° C. to about 75° C.

In some embodiments, converting the acetonitrile solvate of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureais conducted at a reduced pressure of about 35 mm Hg or less at a firsttemperature of about 20° C. to about 30° C. until a loss on drying (LOD)for a representative sample from the process is at a level of about 10%or less; and thereafter raising the first temperature to a secondtemperature of about 65° C. to about 75° C. while maintaining thereduced pressure of about 35 mm Hg or less.

3. Preparation of an acetonitrile solvate of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea

As described herein, supra, the acetonitrile solvate of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureacan be used as an intermediate to prepare Form I of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea.The present invention also discloses processes for preparing theacetonitrile solvate of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea.

Accordingly, one aspect of the present invention relates to processesfor preparing an acetonitrile solvate of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureacomprising the steps of:

a) reacting 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylaminewith 2,4-difluorophenyl-isocyanate in the presence of acetonitrile toform a reaction mixture comprising1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea;and

b) crystallizing the1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureafrom the reaction mixture to form the acetonitrile solvate of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea,the general process is illustrated in Scheme 1 below.

The starting material shown in Scheme 1,3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine, can beprepared by a variety of suitable methods, for examples, such as thosedescribed in PCT Applications PCT/US2004/023880 and PCT/US2006/002721,both of which are incorporated herein by reference in their entirety. Inaddition to these methods,3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine can also beprepared by the novel processes described herein that utilize, ingeneral, an inorganic base in the presence of a mixture comprising anaromatic solvent and an C₁-C₆ alkanol.

In some embodiments, the acetonitrile solvate of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureahas a molecular ratio of acetonitrile to1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureaof about 1:2.

In some embodiments, reacting3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine with2,4-difluorophenyl-isocyanate is conducted under a nitrogen atmosphere.

In some embodiments, reacting3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine with2,4-difluorophenyl-isocyanate is conducted in the presence of about 10%of H₂O or less. In some embodiments, reacting3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine with2,4-difluorophenyl-isocyanate is conducted in the presence of about 1%of H₂O or less. In some embodiments, reacting3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine with2,4-difluorophenyl-isocyanate is conducted in the presence of about 0.1%of H₂O or less.

In some embodiments, reacting3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine with2,4-difluorophenyl-isocyanate is conducted at a temperature of about−30° C. to about 10° C. In some embodiments, reacting3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine with2,4-difluorophenyl-isocyanate is conducted at a temperature of about−25° C. to about 0° C. In some embodiments, reacting3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine with2,4-difluorophenyl-isocyanate is conducted at a temperature of about−15° C. to about −5° C.

In some embodiments, reacting3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine with2,4-difluorophenyl-isocyanate is conducted by adding the2,4-difluorophenyl-isocyanate to the3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine inacetonitrile to form the reaction mixture.

In some embodiments, the reaction mixture comprises less than about 2%of the 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine withrespect to the1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureaas determined by HPLC. In some embodiments, the reaction mixturecomprises less than about 1% of the3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine with respectto the1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureaas determined by HPLC. In some embodiments, the reaction mixturecomprises less than about 0.1% of the3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine with respectto the1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureaas determined by HPLC.

In some embodiments, adding 2,4-difluorophenyl-isocyanate is conductedat a rate sufficient to form the reaction mixture, wherein the reactionmixture comprises less than about 2% of the3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine with respectto the1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureaas determined by HPLC. In some embodiments, adding2,4-difluorophenyl-isocyanate is conducted at a rate sufficient to formthe reaction mixture, wherein the reaction mixture comprises less thanabout 1% of the3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine with respectto the1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureaas determined by HPLC. In some embodiments, adding2,4-difluorophenyl-isocyanate is conducted at a rate sufficient to formthe reaction mixture, wherein the reaction mixture comprises less thanabout 0.1% of the3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine with respectto the1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureaas determined by HPLC.

In some embodiments, after the completion of adding2,4-difluorophenyl-isocyanate, the reaction mixture is stirred untilabout 2% or less of the3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine is present inthe reaction mixture with respect to the1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureaas determined by HPLC. In some embodiments, after the completion ofadding 2,4-difluorophenyl-isocyanate, the reaction mixture is stirreduntil about 1% or less of the3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine is present inthe reaction mixture with respect to the1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureaas determined by HPLC. In some embodiments, after the completion ofadding 2,4-difluorophenyl-isocyanate, the reaction mixture is stirreduntil about 0.1% or less of the3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine is present inthe reaction mixture with respect to the1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureaas determined by HPLC.

Any suitable reverse or normal phase HPLC method can be used determinethe percentage of3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine compared to1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureaprovided that the methods afford at least baseline resolution betweenthe 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine HPLCsignal and the1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureaHPLC signal. One particularly useful method is as follows:

RP-HPLC: HPLC system, equipped with a detector, column oven, quaternarygradient pump, and auto sampler, such as an HPLC system form WatersInc., Milford, Mass. or an equivalent. Detection wavelength set to 252nm. The RP HPLC column is a Waters Symmetry Shield RP18, 3.5 μm, 4.6×150mm or equivalent with a pre-column filter 0.5 μm (Upchurch Scientific).The run time is 37 minutes with an equilibration time of 5 minutes andan injection volume of 5 μL. The mobile phases include, Mobile Phase A:0.1% TFA in water and Mobile Phase B: 0.1% TFA in Acetonitrile. Thegradient is as follows:

Time (min) Flow Rate (mL/min) % A % B Curve 0.00 1.00 90 10 6 10.00 1.0060 40 6 25.00 1.00 45 55 6 30.00 1.00 10 90 6 32.00 1.00 10 90 1 37.001.00 85 15 1The retention time for3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine using thismethod is about 5.4 minutes (relative retention time of 0.24) with arelative response factor of 0.23. The retention time for1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureausing this method is about 22.9 minutes (relative retention time of 1)with a relative response factor of 1.

In some embodiments, after the completion of adding2,4-difluorophenyl-isocyanate, the reaction mixture is stirred for about2 hours or less. In some embodiments, after the completion of adding2,4-difluorophenyl-isocyanate, the reaction mixture is stirred for about1.5 hours or less.

In some embodiments, crystallizing1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureais conducted at a temperature of about −30° C. to about 15° C. In someembodiments, crystallizing1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureais conducted at a temperature of about −25° C. to about 5° C. In someembodiments, crystallizing1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureais conducted at a temperature of about −15° C. to about 0° C. In someembodiments, crystallizing1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureais conducted at a temperature of about −10° C. to about −5° C.

In some embodiments, the process comprises:

reacting 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine with2,4-difluorophenyl-isocyanate in the presence of acetonitrile isconducted by adding 2,4-difluorophenyl-isocyanate to3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine at atemperature of about −25° C. to about 0° C. and a rate sufficient toform the reaction mixture, wherein the reaction mixture comprises lessthan about 2% of3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine with respectto1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureaas determined by HPLC; and

crystallizing1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureais conducted at a temperature of about −15° C. to about 0° C.

In some embodiments the process further comprises the step of isolatingthe acetonitrile. solvate of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea.

In some embodiments, isolating is conducted by filtration of theacetonitrile solvate of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureafrom the reaction mixture.

4. Preparation of3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine fromN-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-acetamide

The compound 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamineis an intermediate useful in the preparation of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea(Compound I), crystalline forms and solvate forms thereof. There is acontinuing effort to develop new processes for intermediates such as3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine that haveimprove efficiency with economic benefit and/or improved product purity.Novel processes for preparing3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine are describedherein. The general process is illustrated in Scheme 2 below.

The starting material shown in Scheme 2,N-[4-methoxy-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-acetamide, can beprepared by a variety of suitable methods, for examples, such as thosedescribed in PCT Applications PCT/US2004/023880 and PCT/US2006/002721,both of which are incorporated herein by reference in their entirety.

Accordingly, one aspect of the present invention relates to processesfor preparing3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine, the processcomprising:

reactingN-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-acetamide withan inorganic base in the presence of a mixture of an aromatic solventand a C₁-C₆ alkanol to form3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine.

In some embodiments, reactingN-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-acetamide withthe inorganic base is conducted at a temperature of about 75° C. toabout reflux temperature. In some embodiments, reactingN-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-acetamide withthe inorganic base is conducted at a temperature of about 100° C. toabout reflux temperature. In some embodiments, reactingN-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-acetamide withthe inorganic base is conducted at a temperature of about 105° C. toabout reflux temperature. In some embodiments, reactingN-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-acetamide withthe inorganic base is conducted at a temperature of about 110° C. toabout reflux temperature. In some embodiments, reactingN-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-acetamide withthe inorganic base is conducted at a temperature of about 112° C.

ReactingN-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-acetamide canbe performed in the presence of a suitable inorganic base. Suitableinorganic bases include alkali metal hydroxides and alkaline earthhydroxides. Examples of suitable bases include lithium hydroxide, sodiumhydroxide, potassium hydroxide and the like.

In some embodiments, the inorganic base is an alkali metal hydroxide. Insome embodiments, the inorganic base is sodium hydroxide.

Although reactingN-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-acetamide withan inorganic base can be conducted in the presence of water, oneembodiment is directed to processes conducted without added water.Residual water present in reagents and solvents is excluded as “added”water in the context of this description. Accordingly, in someembodiments, reactingN-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-acetamide withan inorganic base is conducted in the presence of about 5% or less ofwater. In some embodiments, reactingN-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-acetamide withan inorganic base is conducted in the presence of about 4% or less ofwater. In some embodiments, reactingN-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-acetamide withan inorganic base is conducted in the presence of about 3% or less ofwater. In some embodiments, reactingN-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-acetamide withan inorganic base is conducted in the presence of about 2% or less ofwater. In some embodiments, reactingN-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-acetamide withan inorganic base is conducted in the presence of about 1% or less ofwater. In some embodiments, reactingN-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-acetamide withan inorganic base is conducted in the presence of about 0.5% or less ofwater.

In some embodiments, the aromatic solvent is xylene. In someembodiments, the aromatic solvent is a mixture of xylenes.

In some embodiments, the C₁-C₆ alkanol is n-propanol.

In some embodiments, the aromatic solvent is a mixture of xylenes andthe C₁-C₆ alkanol is n-propanol. In some embodiments, the volume ratioof the mixture of xylenes to n-propanol is about 7:1 to about 1:1. Insome embodiments, the volume ratio of the mixture of xylenes ton-propanol is about 6:1 to about 4:1. In some embodiments, the volumeratio of the mixture of xylenes to n-propanol is about 5:1.

In some embodiments, the process comprises:

reactingN-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-acetamide withthe inorganic base is conducted at a temperature of about 75° C. toabout reflux temperature;

and wherein:

the inorganic base is sodium hydroxide;

the aromatic solvent is a mixture of xylenes; and

the C₁-C₆ alkanol is n-propanol; wherein the volume ratio of the mixtureof xylenes to n-propanol is about 5:1.

Particular processes that are useful for preparingN-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-acetamide aredescribed herein.

Accordingly, in some embodiments,N-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-acetamide isprepared by the process comprising:

reacting N-[4-methoxy-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-acetamidewith a brominating agent in the presence of a brominating solvent toform theN-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-acetamide, thegeneral process is illustrated in Scheme 3 below.

The starting material shown in Scheme 3,N-[4-methoxy-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-acetamide, can beprepared by a variety of suitable methods, for examples, such as thosedescribed in PCT Applications PCT/US2004/023880 and PCT/US2006/002721,both of which are incorporated herein by reference in their entirety.

In some embodiments, reactingN-[4-methoxy-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-acetamide with thebrominating agent is conducted at a temperature of about 25° C. to about100° C. In some embodiments, reactingN-[4-methoxy-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-acetamide with thebrominating agent is conducted at a temperature of about 25° C. to about75° C. In some embodiments, reactingN-[4-methoxy-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-acetamide with thebrominating agent is conducted at a temperature of about 25° C. to about65° C. In some embodiments, reactingN-[4-methoxy-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-acetamide with thebrominating agent is conducted at a temperature of about 35° C. to about65° C.

In some embodiments, reactingN-[4-methoxy-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-acetamide with thebrominating agent is conducted under a nitrogen atmosphere.

In some embodiments, reactingN-[4-methoxy-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-acetamide with thebrominating agent is conducted by adding the brominating agent to theN-[4-methoxy-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-acetamide in thebrominating solvent.

Any suitable brominating agent can be used in the aforementioned processto prepareN-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-acetamide.Suitable brominating agents include, for example, Br₂,N-bromosuccinimide (NBS), 1,3-dibromo-5,5-dimethylhydantoin, pyridiniumtribromide (pyrHBr₃) and the like.

In some embodiments, the brominating agent is N-bromosuccinimide.

The molar ratio of brominating agent toN-[4-methoxy-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-acetamide canroutinely be selected or optimized by the skilled artisan. In generalthe brominating agent is presence in excess compared toN-[4-methoxy-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-acetamide. In someembodiments, the molar ratio of brominating agent toN-[4-methoxy-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-acetamide is selectedfrom about 2:1, about 1.9:1, about 1.8:1, about 1.7:1, about 1.6:1,about 1.5:1, about 1.4:1, about 1.3:1, about 1.2:1, about 1.1:1 andabout 1:1.

Any suitable brominating solvent can be used in the aforementionedprocess to prepareN-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-acetamideprovided that each reagent in the process is sufficiently soluble in thebrominating solvent. Suitable brominating solvents include, for example,N,N-dimethylacetamide, N,N-dimethylformamide and the like.

In some embodiments, the brominating solvent is N,N-dimethylacetamide.

In some embodiments, the brominating agent is N-bromosuccinimide and thebrominating solvent is N,N-dimethylacetamide.

In some embodiments, the process comprises:

reacting N-[4-methoxy-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-acetamidewith the brominating agent is conducted at a temperature of about 35° C.to about 65° C.;

the brominating agent is N-bromosuccinimide; and

the brominating solvent is N,N-dimethylacetamide.

5. Preparation of1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureafrom 3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine

Also provided in the present invention are novel processes for thepreparation of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureathat utilize the step of preparing3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine fromN-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-acetamide.

Accordingly, one aspect of the present invention relates to processesfor preparing1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureacomprising the steps of:

reactingN-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-acetamide withan inorganic base in the presence of a mixture of an aromatic solventand a C₁-C₆ alkanol to form3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine; and

reacting 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine with2,4-difluorophenyl-isocyanate in the presence of a urea-forming solventto form1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea.

Another aspect of the present invention relates to processes forpreparing1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureacomprising the steps of:

a) reacting N-[4-methoxy-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-acetamidewith a brominating agent in the presence of a brominating solvent toform theN-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-acetamide;

b) reactingN-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-acetamide withan inorganic base in the presence of a mixture of an aromatic solventand a C₁-C₆ alkanol to form3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine; and

c) reacting 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylaminewith 2,4-difluorophenyl-isocyanate in the presence of a urea-formingsolvent to form1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea.

5a. Formation ofN-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-acetamide fromN-[4-methoxy-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-acetamide

In some embodiments, reactingN-[4-methoxy-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-acetamide with thebrominating agent is conducted at a temperature of about 25° C. to about100° C. In some embodiments, reactingN-[4-methoxy-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-acetamide with thebrominating agent is conducted at a temperature of about 25° C. to about75° C. In some embodiments, reactingN-[4-methoxy-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-acetamide with thebrominating agent is conducted at a temperature of about 25° C. to about65° C. In some embodiments, reactingN-[4-methoxy-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-acetamide with thebrominating agent is conducted at a temperature of about 35° C. to about65° C.

In some embodiments, reactingN-[4-methoxy-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-acetamide with thebrominating agent is conducted under a nitrogen atmosphere.

In some embodiments, reactingN-[4-methoxy-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-acetamide with thebrominating agent is conducted by adding the brominating agent to theN-[4-methoxy-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-acetamide in thebrominating solvent.

Any suitable brominating agent can be used in the aforementionedprocesses to prepareN-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-acetamide.Suitable brominating agents include, for example, Br₂,N-bromosuccinimide (NBS), 1,3-dibromo-5,5-dimethylhydantoin, pyridiniumtribromide (pyrHBr₃) and the like.

In some embodiments, the brominating agent is N-bromosuccinimide.

The molar ratio of brominating agent toN-[4-methoxy-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-acetamide canroutinely be selected or optimized by the skilled artisan. In generalthe brominating agents is presence in excess compared toN-[4-methoxy-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-acetamide. In someembodiments, the molar ratio of brominating agent toN-[4-methoxy-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-acetamide is selectedfrom about 2:1, about 1.9:1, about 1.8:1, about 1.7:1, about 1.6:1,about 1.5:1, about 1.4:1, about 1.3:1, about 1.2:1, about 1.1:1 andabout 1:1.

Any suitable brominating solvent can be used in the aforementionedprocesses to prepareN-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-acetamideprovided that each reagent in the process is sufficiently soluble in thebrominating solvent. Suitable brominating solvents include, for example,N,N-dimethylacetamide, N,N-dimethylformamide, tetrahydrofuran and thelike.

In some embodiments, the brominating solvent is N,N-dimethylacetamide.

In some embodiments, the brominating agent is N-bromosuccinimide and thebrominating solvent is N,N-dimethylacetamide.

In some embodiments, the process comprises:

reacting N-[4-methoxy-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-acetamidewith the brominating agent is conducted at a temperature of about 35° C.to about 65° C.; the brominating agent is N-bromosuccinimide; and

the brominating solvent is N,N-dimethylacetamide.

5b. Formation of3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine fromN-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-acetamide

In some embodiments, reactingN-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-acetamide withthe inorganic base is conducted at a temperature of about 75° C. toabout reflux temperature. In some embodiments, reactingN-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-acetamide withthe inorganic base is conducted at a temperature of about 100° C. toabout reflux temperature. In some embodiments, reactingN-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-acetamide withthe inorganic base is conducted at a temperature of about 105° C. toabout reflux temperature. In some embodiments, reactingN-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-acetamide withthe inorganic base is conducted at a temperature of about 110° C. toabout reflux temperature. In some embodiments, reactingN-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-acetamide withthe inorganic base is conducted at a temperature of about 112° C.

ReactingN-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-acetamide canbe performed in the presence of any suitable inorganic base. Suitableinorganic bases include alkali metal hydroxides and alkaline earthhydroxides. Examples of suitable inorganic bases include lithiumhydroxide, sodium hydroxide, potassium hydroxide and the like.

In some embodiments, the inorganic base is an alkali metal hydroxide. Insome embodiments, the inorganic base is sodium hydroxide.

Although reactingN-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-acetamide withan inorganic base can be conducted in the presence of water, oneembodiment is directed to processes conducted without added water.Residual water present in reagents and solvents is excluded as “added”water in the context of this description. Accordingly, in someembodiments, reactingN-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-acetamide withan inorganic base is conducted in the presence of about 5% or less ofwater. In some embodiments, reactingN-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-acetamide withan inorganic base is conducted in the presence of about 4% or less ofwater. In some embodiments, reactingN-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-acetamide withan inorganic base is conducted in the presence of about 3% or less ofwater. In some embodiments, reactingN-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-acetamide withan inorganic base is conducted in the presence of about 2% or less ofwater. In some embodiments, reactingN-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-acetamide withan inorganic base is conducted in the presence of about 1% or less ofwater. In some embodiments, reactingN-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-acetamide withan inorganic base is conducted in the presence of about 0.5% or less ofwater.

In some embodiments, the aromatic solvent is xylene. In someembodiments, the aromatic solvent is a mixture of xylenes.

In some embodiments, the C₁-C₆ alkanol is n-propanol.

In some embodiments, the aromatic solvent is a mixture of xylenes andC₁-C₆ alkanol is n-propanol.

In some embodiments, the volume ratio of the mixture of xylenes ton-propanol is about 7:1 to about 1:1. In some embodiments, the volumeratio of the mixture of xylenes to n-propanol is about 6:1 to about 4:1.In some embodiments, the volume ratio of the mixture of xylenes ton-propanol is about 5:1.

In some embodiments, the process comprises:

reactingN-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-acetamide withthe inorganic base is conducted at a temperature of about 75° C. toabout reflux temperature; and

wherein:

the inorganic base is sodium hydroxide;

the aromatic solvent is a mixture of xylenes; and

the C₁-C₆ alkanol is n-propanol; wherein the volume ratio of the mixtureof xylenes to n-propanol is about 5:1.

5c. Formation of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureafrom 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine

In some embodiments, reacting3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine with2,4-difluorophenyl-isocyanate is conducted under a nitrogen atmosphere.

In some embodiments, reacting3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine with2,4-difluorophenyl-isocyanate is conducted in the presence of about 10%of H₂O or less. In some embodiments, reacting3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine with2,4-difluorophenyl-isocyanate is conducted in the presence of about 1%of H₂O or less. In some embodiments, reacting3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine with2,4-difluorophenyl-isocyanate is conducted in the presence of about 0.1%of H₂O or less.

In some embodiments, reacting3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine with2,4-difluorophenyl-isocyanate is conducted at a temperature of about−30° C. to about 10° C. In some embodiments, reacting3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine with2,4-difluorophenyl-isocyanate is conducted at a temperature of about−25° C. to about 0° C. In some embodiments, reacting3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine with2,4-difluorophenyl-isocyanate is conducted at a temperature of about−15° C. to about −5° C.

In some embodiments, reacting3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine with2,4-difluorophenyl-isocyanate is conducted by adding the2,4-difluorophenyl-isocyanate to the3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine inacetonitrile to form a reaction mixture.

In some embodiments, the reaction mixture comprises less than about 2%of the 3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine withrespect to the1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureaas determined by HPLC. In some embodiments, the reaction mixturecomprises less than about 1% of the3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine with respectto the1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureaas determined by HPLC. In some embodiments, the reaction mixturecomprises less than about 0.1% of the3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine with respectto the1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureaas determined by HPLC.

In some embodiments, adding 2,4-difluorophenyl-isocyanate is conductedat a rate sufficient to form the reaction mixture, wherein the reactionmixture comprises less than about 2% of the3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine with respectto the1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureaas determined by HPLC. In some embodiments, adding2,4-difluorophenyl-isocyanate is conducted at a rate sufficient to formthe reaction mixture, wherein the reaction mixture comprises less thanabout 1% of the3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine with respectto the1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureaas determined by HPLC. In some embodiments, adding2,4-difluorophenyl-isocyanate is conducted at a rate sufficient to formthe reaction mixture, wherein the reaction mixture comprises less thanabout 0.1% of the3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine with respectto the1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureaas determined by HPLC.

In some embodiments, after the completion of adding2,4-difluorophenyl-isocyanate, the reaction mixture is stirred untilabout 2% or less of the3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine is present inthe reaction mixture with respect to the1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureaas determined by HPLC. In some embodiments, after the completion ofadding 2,4-difluorophenyl-isocyanate, the reaction mixture is stirreduntil about 1% or less of the3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine is present inthe reaction mixture with respect to the1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureaas determined by HPLC. In some embodiments, after the completion ofadding 2,4-difluorophenyl-isocyanate, the reaction mixture is stirreduntil about 0.1% or less of the3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine is present inthe reaction mixture with respect to the1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureaas determined by HPLC.

In some embodiments, after the completion of adding2,4-difluorophenyl-isocyanate, the reaction mixture is stirred for about2 hours or less. In some embodiments, after the completion of adding2,4-difluorophenyl-isocyanate, the reaction mixture is stirred for about1.5 hours or less.

In some embodiments the process further comprises the step of isolatingthe1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureafrom the reaction mixture comprising1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureaand the urea-forming solvent. In some embodiments, the isolating isconducted by filtration of the1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureafrom the reaction mixture comprising1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureaand the urea-forming solvent.

Any suitable urea-forming solvent can be used in the aforementionedprocess to prepare1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea.Representative urea-forming solvents include but not limited to aromaticsolvents (e.g., benzene, toluene, and the like), N,N-dimethylformamide(DMF), N,N-dimethylacetamide (DMA), methylsulfoxide, acetonitrile, ethylacetate, methylene chloride, mixtures thereof and the like. Oneparticularly useful solvent is acetonitrile as this solvent providesadvantages over other solvents, such as, providing the acetonitrilesolvate that can be converted to Form I of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea.

In some embodiments, the urea-forming solvent is acetonitrile.

In some embodiments the process further comprises the step ofcrystallizing the1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureafrom the reaction mixture to form a acetonitrile solvate of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea.

In some embodiments, the acetonitrile solvate of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureahas a molecular ratio of acetonitrile to1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureaof about 1:2.

In some embodiments, the crystallizing is conducted at a temperature ofabout −30° C. to about 15° C. In some embodiments, the crystallizing isconducted at a temperature of about −25° C. to about 5° C. In someembodiments, the crystallizing is conducted at a temperature of about−15° C. to about 0° C. In some embodiments, the crystallizing isconducted at a temperature of about −10° C. to about −5° C.

In some embodiments the process further comprises the step of isolatingthe acetonitrile solvate of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea.In some embodiments, the isolating is conducted by filtration of theacetonitrile solvate of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureafrom the reaction mixture.

In some embodiments the process further comprises the step of convertingthe acetonitrile solvate of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea.

In some embodiments the process further comprises the step of convertingthe acetonitrile solvate of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureato form I of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea.

In some embodiments, the converting of the acetonitrile solvate of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureais conducted under reduced pressure.

In some embodiments, the converting of the acetonitrile solvate of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureais conducted at a reduced pressure of about 100 mm Hg or less. In someembodiments, the converting of the acetonitrile solvate of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureais conducted at a reduced pressure of about 35 mm Hg or less. In someembodiments, the converting of the acetonitrile solvate of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureais conducted at a reduced pressure of about 10 mm Hg or less. In someembodiments, the converting of the acetonitrile solvate of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureais conducted at a reduced pressure of about 5 mm Hg or less.

In some embodiments, converting the acetonitrile solvate of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureais conducted during at least two time periods, wherein the conversion isconducted at a first temperature during a first time period and whereinthe conversion is conducted at a second temperature during a second timeperiod, and wherein the first temperature is not equivalent to thesecond temperature.

In some embodiments, the second temperature is higher than the firsttemperature. In some embodiments, the first temperature is at about 0°C. to about 45° C. In some embodiments, the first temperature is atabout 15° C. to about 40° C. In some embodiments, the first temperatureis at about 20° C. to about 30° C.

In some embodiments, the second temperature is about 45° C. to about 90°C. In some embodiments, the second temperature is about 60° C. to about80° C. In some embodiments, the second temperature is about 65° C. toabout 75° C.

In some embodiments, the first temperature is at about 20° C. to about30° C. and the second temperature is about 65° C. to about 75° C.

In some embodiments the process further comprises the step ofmaintaining the first temperature until a loss on drying (LOD) for arepresentative sample from the process is at a level of about 30% orless. In some embodiments the process further comprises the step ofmaintaining the first temperature until a loss on drying (LOD) for arepresentative sample from the process is at a level of about 20% orless. In some embodiments the process further comprises the step ofmaintaining the first temperature until a loss on drying (LOD) for arepresentative sample from the process is at a level of about 15% orless. In some embodiments the process further comprises the step ofmaintaining the first temperature until a loss on drying (LOD) for arepresentative sample from the process is at a level of about 10% orless.

In some embodiments, converting the acetonitrile solvate of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureais conducted at a first temperature of about 0° C. to about 45° C. untila loss on drying (LOD) for a representative sample from the process isat a level of about 30% or less and thereafter raising to a secondtemperature of about 45° C. to about 90° C. In some embodiments,converting the acetonitrile solvate of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureais conducted at a first temperature of about 15° C. to about 40° C.until a loss on drying (LOD) for a representative sample from theprocess is at a level of about 20% or less and thereafter raising to asecond temperature about 60° C. to about 80° C. In some embodiments,converting the acetonitrile solvate of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureais conducted at a first temperature of about 20° C. to about 30° C.until a loss on drying (LOD) for a representative sample from theprocess is at a level of about 15% or less and thereafter raising to asecond temperature of about 60° C. to about 80° C. In some embodiments,converting the acetonitrile solvate of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureais conducted at a first temperature of about 20° C. to about 30° C.until a loss on drying (LOD) for a representative sample from theprocess is at a level of about 10% or less and thereafter raising to asecond temperature of about 65° C. to about 75° C.

In some embodiments, converting the acetonitrile solvate of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureais conducted at a reduced pressure of about 35 mm Hg or less at a firsttemperature of about 20° C. to about 30° C. until a loss on drying (LOD)for a representative sample from the process is at a level of about 10%or less; and thereafter raising the first temperature to a secondtemperature of about 65° C. to about 75° C. while maintaining thereduced pressure of about 35 mm Hg or less.

6. Preparation of Form I of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea

Also provided in the present invention are processes that areparticularly useful for reprocessing/recrystallizing1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureathat may have undesirable levels of impurities, polymorphs,contaminants, reagents, solvents or the like to give Form I of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea.These processes can utilize a variety of physical forms of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureaas the starting material, for example, Form I, Form II, Form IV,amorphous material or mixtures thereof.

Accordingly, the present invention relates to processes for preparingForm I of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea,the process comprising:

a) dissolving1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureain tetrahydrofuran to form a solution;

b) adding an aliphatic solvent to the solution to form a mixturecomprising a first solvate of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea;

c) isolating the first solvate of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureafrom the mixture to provide an isolated first solvate of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea;and

d) converting the isolated first solvate to provide Form I of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea.This embodiment provides processes that give Form I of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureawith good purity and under certain circumstances these processes areacceptable if trace amounts of aliphatic solvent can be tolerated.However, in the example where the aliphatic solvent is heptane, ICHguidelines suggest that the maximum level of heptane to be about 5000ppm. As a result, it was found that by washing the first solvate of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureawith acetonitrile provided a second solvate that could subsequently beconverted to Form I of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureawith solvent levels below ICH guidelines.

Accordingly, another aspect of the present invention relates toprocesses for preparing Form I of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea,the process comprising:

a) dissolving1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureain tetrahydrofuran to form a solution;

b) adding an aliphatic solvent to the solution to form a mixturecomprising a first solvate of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea;

c) isolating the first solvate of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureafrom the mixture to provide an isolated first solvate of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea;

d) washing the isolated first solvate of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureawith acetonitrile to form a second solvate of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea;and

e) converting the second solvate to provide Form I of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea.

In some embodiments, the dissolving1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureain tetrahydrofuran is conducted at a weight ratio of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureato tetrahydrofuran of about 1:6 to about 1:5. In some embodiments, thedissolving1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureain tetrahydrofuran is conducted at a weight ratio of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureato tetrahydrofuran of about 1.3:5.6. In some embodiments, the dissolving1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureain tetrahydrofuran is conducted at a temperature of about 25° C. toabout reflux temperature.

In some embodiments, the dissolving1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureain tetrahydrofuran is conducted at a temperature of about 55° C. toabout reflux temperature. In some embodiments, the dissolving1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureain tetrahydrofuran is conducted at a temperature of about 60° C. toabout reflux temperature. In some embodiments, the dissolving1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureain tetrahydrofuran is conducted at or about reflux temperature. In someembodiments the process further comprises the step of cooling thesolution of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureain tetrahydrofuran in step a) prior to step b).

In some embodiments, the cooling is to a temperature of about −35° C. toabout 10° C. In some embodiments, the cooling is to a temperature ofabout −25° C. to about −5° C.

In some embodiments, adding heptane to the solution to form a firstsolvate of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureais conducted at a temperature of about −35° C. to about 10° C. In someembodiments, adding heptane to the solution to form a first solvate of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureais conducted at a temperature of about −25° C. to about −5° C.

In some embodiments, the aliphatic solvent is a C₅-C₁₀ alkane, a C₅-C₈cycloalkane or a mixture thereof. In some embodiments, the aliphaticsolvent is a C₅-C₁₀ alkane. In some embodiments, the aliphatic solventis hexane. In some embodiments, the aliphatic solvent is cyclohexane. Insome embodiments, the aliphatic solvent is heptane.

It is understood that the mixture obtained by the addition of heptanecomprises at least a tetrahydrofuran solvate or a heptane solvate or amixture of these two solvates. In addition, there may be other solvatesthat are present in the mixture that have not been identified. Thetetrahydrofuran solvate and the heptane solvate have been identified.The powder X-ray diffraction (PXRD) pattern for the tetrahydrofuransolvate of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureais shown in FIG. 29. The powder X-ray diffraction (PXRD) pattern for theheptane solvate of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureais shown in FIG. 30.

In some embodiments, the first solvate is a tetrahydrofuran solvate.

In some embodiments, the first solvate is a heptane solvate.

In some embodiments, adding the aliphatic solvent to the solution toform a mixture comprising a first solvate of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureais conducted at a temperature of about −35° C. to about 10° C.

In some embodiments, adding the aliphatic solvent to the solution toform a mixture comprising a first solvate of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureais conducted at a temperature of about −25° C. to about −5° C.

In some embodiments, isolating the first solvate of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureafrom the mixture is conducted by filtration to provide the isolatedfirst solvate of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea.

In some embodiments, washing the isolated first solvate of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureawith acetonitrile is conducted at a temperature of about −20° C. toabout 10° C. to form a second solvate of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea.In some embodiments, washing the isolated first solvate of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureawith acetonitrile is conducted at a temperature of about −10° C. toabout 10° C. to form a second solvate of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea.In some embodiments, washing the isolated first solvate of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureawith acetonitrile is conducted at a temperature of about −5° C. to about5° C. to form a second solvate of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea.

In some embodiments, the second solvate is an acetonitrile solvate of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea.Additional information for converting the acetonitrile solvate to Form Iof1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureahas been described supra, also see the Examples infra.

In some embodiments, the acetonitrile solvate of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureahas a molecular ratio of acetonitrile to1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureaof about 1:2.

In some embodiments, converting the second solvate to provide Form I of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureais conducted under reduced pressure. In some embodiments, converting thesecond solvate to provide Form I of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureais conducted at a reduced pressure of about 100 mm Hg or less. In someembodiments, converting the second solvate to provide Form I of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureais conducted at a reduced pressure of about 35 mm Hg or less. In someembodiments, converting the second solvate to provide Form I of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureais conducted at a reduced pressure of about 10 mm Hg or less. In someembodiments, converting the second solvate to provide Form I of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureais conducted at a reduced pressure of about 5 mm Hg or less. In someembodiments, converting the second solvate to provide Form I of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureais conducted during at least two time periods, wherein the conversion isconducted at a first temperature during a first time period and whereinthe conversion is conducted at a second temperature during a second timeperiod, and wherein the first temperature is not equivalent to thesecond temperature.

In some embodiments, the second temperature is higher than the firsttemperature.

In some embodiments, the first temperature is at about 0° C. to about45° C. In some embodiments, the first temperature is at about 15° C. toabout 40° C. In some embodiments, the first temperature is at about 20°C. to about 30° C.

In some embodiments, the second temperature is about 45° C. to about 90°C. In some embodiments, the second temperature is about 60° C. to about80° C. In some embodiments, the second temperature is about 65° C. toabout 75° C.

In some embodiments, the first temperature is at about 20° C. to about30° C. and the second temperature is about 65° C. to about 75° C.

In some embodiments the process further comprises the step ofmaintaining the first temperature until a loss on drying (LOD) for arepresentative sample from the process is at a level of about 30% orless. In some embodiments the process further comprises the step ofmaintaining the first temperature until a loss on drying (LOD) for arepresentative sample from the process is at a level of about 20% orless. In some embodiments the process further comprises the step ofmaintaining the first temperature until a loss on drying (LOD) for arepresentative sample from the process is at a level of about 15% orless. In some embodiments the process further comprises the step ofmaintaining the first temperature until a loss on drying (LOD) for arepresentative sample from the process is at a level of about 10% orless.

In some embodiments, converting the second solvate to provide Form I of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureais conducted at a first temperature of about 0° C. to about 45° C. untila loss on drying (LOD) for a representative sample from the process isat a level of about 30% or less and thereafter raising to a secondtemperature of about 45° C. to about 90° C. In some embodiments,converting the second solvate to provide Form I of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureais conducted at a first temperature of about 15° C. to about 40° C.until a loss on drying (LOD) for a representative sample from theprocess is at a level of about 20% or less and thereafter raising to asecond temperature about 60° C. to about 80° C. In some embodiments,converting the second solvate to provide Form I of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureais conducted at a first temperature of about 20° C. to about 30° C.until a loss on drying (LOD) for a representative sample from theprocess is at a level of about 15% or less and thereafter raising to asecond temperature of about 60° C. to about 80° C. In some embodiments,converting the second solvate to provide Form I of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureais conducted at a first temperature of about 20° C. to about 30° C.until a loss on drying (LOD) for a representative sample from theprocess is at a level of about 10% or less and thereafter raising to asecond temperature of about 65° C. to about 75° C.

In some embodiments, converting the acetonitrile solvate of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureais conducted at a reduced pressure of about 35 mm Hg or less at a firsttemperature of about 20° C. to about 30° C. until a loss on drying (LOD)for a representative sample from the process is at a level of about 10%or less; and thereafter raising the first temperature to a secondtemperature of about 65° C. to about 75° C. while maintaining thereduced pressure of about 35 mm Hg or less.

7. Compositions and Processes of Preparing Compositions Comprising1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea

One aspect of the present invention relates to compositions comprisingForm I of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureaprepared according to any of the processes described herein, wherein thecomposition comprises less than 0.9 mole % of1-(2,4-difluorophenyl)-3-(4-methoxy-3-(1-methyl-1H-pyrazol-5-yl)phenyl)urea.

1-(2,4-difluorophenyl)-3-(4-methoxy-3-(1-methyl-1H-pyrazol-5-yl)phenyl)urea

Another aspect of the present invention relates to processes forpreparing a pharmaceutical composition comprising admixing:

a composition comprising Form I of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureaprepared according to any one of the processes described herein, whereinthe composition comprises less than 0.9 mole % of1-(2,4-difluorophenyl)-3-(4-methoxy-3-(1-methyl-1H-pyrazol-5-yl)phenyl)urea;and

a pharmaceutically acceptable carrier.

In some embodiments, compositions comprising Form I of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureacontain less than 0.8 mole % of1-(2,4-difluorophenyl)-3-(4-methoxy-3-(1-methyl-1H-pyrazol-5-yl)phenyl)urea.In some embodiments, compositions contain less than 0.7 mole % of1-(2,4-difluorophenyl)-3-(4-methoxy-3-(1-methyl-1H-pyrazol-5-yl)phenyl)urea.In some embodiments, compositions contain less than 0.6 mole % of1-(2,4-difluorophenyl)-3-(4-methoxy-3-(1-methyl-1H-pyrazol-5-yl)phenyl)urea.In some embodiments, compositions contain less than 0.5 mole % of1-(2,4-difluorophenyl)-3-(4-methoxy-3-(1-methyl-1H-pyrazol-5-yl)phenyl)urea.In some embodiments, compositions contain less than 0.4 mole % of1-(2,4-difluorophenyl)-3-(4-methoxy-3-(1-methyl-1H-pyrazol-5-yl)phenyl)urea.In some embodiments, compositions contain less than 0.3 mole % of1-(2,4-difluorophenyl)-3-(4-methoxy-3-(1-methyl-1H-pyrazol-5-yl)phenyl)urea.In some embodiments, compositions contain less than 0.2 mole % of1-(2,4-difluorophenyl)-3-(4-methoxy-3-(1-methyl-1H-pyrazol-5-yl)phenyl)urea.In some embodiments, compositions contain less than 0.1 mole % of1-(2,4-difluorophenyl)-3-(4-methoxy-3-(1-methyl-1H-pyrazol-5-yl)phenyl)urea.

Any suitable method can be used to determine the mol % of1-(2,4-difluorophenyl)-3-(4-methoxy-3-(1-methyl-1H-pyrazol-5-yl)phenyl)urea,for example, ¹H NMR, HPLC, and the like. The HPLC method described abovealong with the relative response factor (or by running standardconcentration curves) is particularly useful for determining the mol %of1-(2,4-difluorophenyl)-3-(4-methoxy-3-(1-methyl-1H-pyrazol-5-yl)phenyl)urea.

Another aspect of the present invention relates to processes forpreparing a pharmaceutical composition comprising admixing:

a composition comprising1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureaprepared according to any of the processes described herein, wherein thecomposition comprises less than 0.9 mole % of1-(2,4-difluorophenyl)-3-(4-methoxy-3-(1-methyl-1H-pyrazol-5-yl)phenyl)urea;and

a pharmaceutically acceptable carrier.

Another aspect of the present invention relates to compositionscomprising an acetonitrile solvate of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureaprepared according to any of the processes described herein.

In some embodiments, the acetonitrile solvate of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureahas a molecular ratio of acetonitrile to1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureaof about 1:2.

Another aspect of the present invention relates to compositionscomprising an acetonitrile solvate of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea.In some embodiments, the acetonitrile solvate of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureahas a molecular ratio of acetonitrile to1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureaof about 1:2.

Pharmaceutical compositions may be prepared by any suitable method,typically by uniformly mixing Form I of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureawith liquids or finely divided solid carriers, or both, in the requiredproportions, and then, if necessary, forming the resulting mixture intoa desired shape.

Accordingly, another aspect of the present invention provide processesfor preparing pharmaceutical compositions comprising admixing Form I of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureaprepared by any of the methods described herein, and a pharmaceuticallyacceptable carrier.

Conventional excipients, such as binding agents, fillers, acceptablewetting agents, tableting lubricants, and disintegrants may be used intablets and capsules for oral administration. Liquid preparations fororal administration may be in the form of solutions, emulsions, aqueousor oily suspensions, and syrups. Alternatively, the oral preparationsmay be in the form of a dry powder that can be reconstituted with wateror another suitable liquid vehicle before use. Additional additives suchas suspending or emulsifying agents, non-aqueous vehicles (includingedible oils), preservatives, and flavorings and colorants may be addedto the liquid preparations. Parenteral dosage forms may be prepared bydissolving the compound of the invention in a suitable liquid vehicleand filter sterilizing the solution before filling and sealing anappropriate vial or ampoule. These are just a few examples of the manyappropriate methods well known in the art for preparing dosage forms.

Form I of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea(Form I hereafter) of the present invention can be formulated intopharmaceutical compositions using techniques well known to those in theart and as described herein. Suitable pharmaceutically-acceptablecarriers, outside those mentioned herein, are known in the art; forexample, see Remington, The Science and Practice of Pharmacy, 20^(th)Ed., 2000, Lippincott Williams & Wilkins, (Editors: Gennaro, A. R., etal.).

While it is possible that Form I of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea(i.e., active ingredient) as described herein may, in an alternativeuse, be administered as a raw or pure chemical, it is preferable howeverto present the active ingredient as a pharmaceutical formulation orcomposition further comprising a pharmaceutically acceptable carrier.The carrier(s) must be “acceptable” in the sense of being compatiblewith the other ingredients of the formulation and not overly deleteriousto the recipient thereof.

Pharmaceutical formulations include those suitable for oral, rectal,nasal, topical (including buccal and sub-lingual), vaginal or parenteral(including intramuscular, subcutaneous and intravenous) administrationor in a form suitable for administration by inhalation, insufflation orby a transdermal patch. Transdermal patches dispense a drug at acontrolled rate by presenting the drug for absorption in an efficientmanner with a minimum of degradation of the drug. Typically, transdermalpatches comprise an impermeable backing layer, a single pressuresensitive adhesive and a removable protective layer with a releaseliner. One of ordinary skill in the art will understand and appreciatethe techniques appropriate for manufacturing a desired efficacioustransdermal patch based upon the needs of the artisan.

The Form I of the present invention, together with a conventionaladjuvant, carrier, or diluent, may be placed into the form ofpharmaceutical formulations and unit dosages thereof, and in such formmay be employed as solids, such as tablets or filled capsules, orliquids such as solutions, suspensions, emulsions, elixirs, gels orcapsules filled with the same, all for oral use, in the form ofsuppositories for rectal administration; or in the form of sterileinjectable solutions for parenteral (including subcutaneous) use. Suchpharmaceutical compositions and unit dosage forms thereof may compriseconventional ingredients in conventional proportions, with or withoutadditional active compounds or principles, and such unit dosage formsmay contain any suitable effective amount of the active ingredientcommensurate with the intended daily dosage range to be employed.

For oral administration, the pharmaceutical composition may be in theform of, for example, a tablet, capsule, suspension or liquid. Thepharmaceutical composition is preferably made in the form of a dosageunit containing a particular amount of the active ingredient. Examplesof such dosage units are capsules, tablets, powders, granules or asuspension, with conventional additives such as lactose, mannitol, cornstarch or potato starch; with binders such as crystalline cellulose,cellulose derivatives, acacia, corn starch or gelatins; withdisintegrators such as corn starch, potato starch or sodiumcarboxymethylcellulose; and with lubricants such as talc or magnesiumstearate. The active ingredient may also be administered by injection asa composition wherein, for example, saline, dextrose or water may beused as a suitable pharmaceutically acceptable carrier.

The dose when using the compounds of the present invention can varywithin wide limits, as is customary and is known to the physician, it isto be tailored to the individual conditions in each individual case. Itdepends, for example, on the nature and severity of the illness to betreated, on the condition of the patient, on the compound employed or onwhether an acute or chronic disease state is treated or prophylaxis isconducted or on whether further active compounds are administered inaddition to Form I of the present invention. Representative doses of thepresent invention include, but are not limited to, about 0.001 mg toabout 5000 mg, about 0.001 mg to about 2500 mg, about 0.001 mg to about1000 mg, 0.001 mg to about 500 mg, 0.001 mg to about 250 mg, about 0.001mg to 100 mg, about 0.001 mg to about 50 mg, and about 0.001 mg to about25 mg. Multiple doses may be administered during the day, especiallywhen relatively large amounts are deemed to be needed, for example 2, 3or 4, doses. Depending on the individual and as deemed appropriate fromthe patient's physician or caregiver it may be necessary to deviateupward or downward from the doses described herein.

The amount of Form I of the present invention, required for use intreatment will vary with the route of administration, the nature of thecondition being treated and the age and condition of the patient andwill ultimately be at the discretion of the attendant physician orclinician. In general, one skilled in the art understands how toextrapolate in vivo data obtained in a model system, typically an animalmodel, to another, such as a human. In some circumstances, theseextrapolations may merely be based on the weight of the animal model incomparison to another, such as a mammal, preferably a human, however,more often, these extrapolations are not simply based on weights, butrather incorporate a variety of factors. Representative factors includethe type, age, weight, sex, diet and medical condition of the patient,the severity of the disease, the route of administration,pharmacological considerations such as the activity, efficacy,pharmacokinetic and toxicology profiles of the particular compoundemployed, whether a drug delivery system is utilized, whether thedisease state is chronic or acute, whether treatment or prophylaxis isconducted, or on whether further active compounds are administered inaddition to Form I of the present invention and as part of a drugcombination. The dosage regimen for treating a disease condition withForm I of the present invention and/or compositions of this invention isselected in accordance with a variety of factors as cited above. Thus,the actual dosage regimen employed may vary widely and therefore maydeviate from a preferred dosage regimen and one skilled in the art willrecognize that dosages and dosage regimens outside these typical rangescan be tested and, where appropriate, may be used in the methods of thisinvention.

The desired dose may conveniently be presented in a single dose or asdivided doses administered at appropriate intervals, for example, astwo, three, four or more sub-doses per day. The sub-dose itself may befurther divided, e.g., into a number of discrete loosely spacedadministrations. The daily dose can be divided, especially whenrelatively large amounts are administered as deemed appropriate, intoseveral, for example 2, 3 or 4, part administrations. If appropriate,depending on individual behavior, it may be necessary to deviate upwardor downward from the daily dose indicated.

Form I of the present invention can be administrated in a wide varietyof oral and parenteral dosage forms.

For preparing pharmaceutical compositions of Form I of the presentinvention, the selection of a suitable pharmaceutically acceptablecarrier can be either solid, liquid or a mixture of both. Solid formpreparations include powders, tablets, pills, capsules, cachets,suppositories, and dispersible granules. A solid carrier can be one ormore substances that may also act as diluents, flavoring agents,solubilizers, lubricants, suspending agents, binders, preservatives,tablet disintegrating agents, or an encapsulating material.

In powders, the carrier is a finely divided solid that is in a mixturewith the finely divided active component.

In tablets, the active component is mixed with the carrier having thenecessary binding capacity in suitable proportions and compacted to thedesired shape and size.

The powders and tablets may contain varying percentage amounts of theactive compound. A representative amount in a powder or tablet maycontain from 0.5 to about 90 percent of Form I of the present invention;however, an artisan of ordinary skill would know when amounts outside ofthis range are necessary. Suitable carriers for powders and tablets aremagnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin,dextrin, starch, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose, a low melting wax, cocoa butter, and the like.The term “preparation” is intended to include the formulation of theactive compound with encapsulating material as carrier providing acapsule in which the active component, with or without carriers, issurrounded by a carrier, which is thus in association with it.Similarly, cachets and lozenges are included. Tablets, powders,capsules, pills, cachets, and lozenges can be used as solid formssuitable for oral administration.

For preparing suppositories, a low melting wax, such as an admixture offatty acid glycerides or cocoa butter, is first melted and the activecomponent is dispersed homogeneously therein, as by stirring. The moltenhomogenous mixture is then poured into convenient sized molds, allowedto cool, and thereby to solidify.

Formulations suitable for vaginal administration may be presented aspessaries, tampons, creams, gels, pastes, foams or sprays containing inaddition to the active ingredient such carriers as are known in the artto be appropriate.

Liquid form preparations include solutions, suspensions, and emulsions,for example, water or water-propylene glycol solutions. For example,parenteral injection liquid preparations can be formulated as solutionsin aqueous polyethylene glycol solution. Injectable preparations, forexample, sterile injectable aqueous or oleaginous suspensions may beformulated according to the known art using suitable dispersing orwetting agents and suspending agents. The sterile injectable preparationmay also be a sterile injectable solution or suspension in a nontoxicparenterally acceptable diluent or solvent, for example, as a solutionin 1,3-butanediol. Among the acceptable vehicles and solvents that maybe employed are water, Ringer's solution, and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas solvents or suspending media. For this purpose, any bland fixed oilmay be employed including synthetic mono- or diglycerides. In addition,fatty acids such as oleic acid find use in the preparation ofinjectables.

Form I of the present invention, may thus be formulated for parenteraladministration (e.g. by injection, for example bolus injection orcontinuous infusion) and may be presented in unit dose form in ampoules,pre-filled syringes, small volume infusion or in multi-dose containerswith an added preservative. The pharmaceutical compositions may takesuch forms as suspensions, solutions, or emulsions in oily or aqueousvehicles, and may contain formulatory agents such as suspending,stabilizing and/or dispersing agents. Alternatively, the activeingredient may be in powder form, obtained by aseptic isolation ofsterile solid or by lyophilization from solution, for constitution witha suitable vehicle, e.g. sterile, pyrogen-free water, before use.

Aqueous formulations suitable for oral use can be prepared by dissolvingor suspending the active component in water and adding suitablecolorants, flavors, stabilizing and thickening agents, as desired.

Aqueous suspensions suitable for oral use can be made by dispersing thefinely divided active component in water with viscous material, such asnatural or synthetic gums, resins, methylcellulose, sodiumcarboxymethylcellulose, or other well-known suspending agents.

Also included are solid form preparations that are intended to beconverted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

For topical administration to the epidermis, Form I of the presentinvention may be formulated as ointments, creams or lotions, or as atransdermal patch.

Ointments and creams may, for example, be formulated with an aqueous oroily base with the addition of suitable thickening and/or gellingagents. Lotions may be formulated with an aqueous or oily base and willgenerally also contain one or more emulsifying agents, stabilizingagents, dispersing agents, suspending agents, thickening agents, orcoloring agents.

Formulations suitable for topical administration in the mouth includelozenges comprising active agent in a flavored base, usually sucrose andacacia or tragacanth; pastilles comprising the active ingredient in aninert base such as gelatin and glycerin or sucrose and acacia; andmouthwashes comprising the active ingredient in a suitable liquidcarrier.

Solutions or suspensions are applied directly to the nasal cavity byconventional means, for example with a dropper, pipette or spray. Theformulations may be provided in single or multi-dose form. In the lattercase of a dropper or pipette, this may be achieved by the patientadministering an appropriate, predetermined volume of the solution orsuspension. In the case of a spray, this may be achieved for example bymeans of a metering atomizing spray pump.

Administration to the respiratory tract may also be achieved by means ofan aerosol formulation in which the active ingredient is provided in apressurized pack with a suitable propellant. Administration to therespiratory tract include, for example, nasal aerosols or by inhalation,this can be carried out, for example, by using a spray, a nebulizer, apump nebulizer, an inhalation apparatus, a metered inhaler or a drypowder inhaler. Pharmaceutical forms for administration of the compoundsof the present invention as an aerosol can be prepared by processes wellknown to the person skilled in the art. For their preparation, forexample, solutions or dispersions of the active ingredient in water,water/alcohol mixtures or suitable saline solutions can be employedusing customary additives, for example benzyl alcohol or other suitablepreservatives, absorption enhancers for increasing the bioavailability,solubilizers, dispersants and others, and, if appropriate, customarypropellants, for example, carbon dioxide, CFCs, such as,dichlorodifluoromethane, trichlorofluoromethane, anddichlorotetrafluoroethane, HFAs, such as,1,1,1,2,3,3,3-heptaflurorpropane and 1,1,1,2-tetrafluoroethane, and thelike. The aerosol may conveniently also contain a surfactant such aslecithin. The dose of drug may be controlled by provision of a meteredvalve.

In formulations intended for administration to the respiratory tract,including intranasal formulations, the compound will generally have asmall particle size for example of the order of 10 microns or less. Sucha particle size may be obtained by means known in the art, for exampleby micronization. When desired, formulations adapted to give sustainedrelease of the active ingredient may be employed.

Alternatively, the active ingredients may be provided in the form of adry powder, for example, a powder mix of the compound in a suitablepowder base such as lactose, starch, starch derivatives such ashydroxypropylmethylcellulose and polyvinylpyrrolidone (PVP).Conveniently the powder carrier will form a gel in the nasal cavity. Thepowder composition may be presented in unit dose form for example incapsules or cartridges of, e.g., gelatin, or blister packs from whichthe powder may be administered by means of an inhaler.

The pharmaceutical preparations are preferably in unit dosage forms. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

Tablets or capsules for oral administration and liquids for intravenousadministration are preferred compositions.

Some embodiments of the present invention include a method of producinga pharmaceutical composition for “combination-therapy” comprisingadmixing at least one compound or crystalline form thereof as disclosedherein, together with at least one known pharmaceutical agent asdescribed herein and a pharmaceutically acceptable carrier.

It is noted that when the serotonin 5-HT_(2A)-receptor modulators areutilized as active ingredients in a pharmaceutical composition, theseare not intended for use only in humans, but in other non-human mammalsas well. Indeed, recent advances in the area of animal health-caresuggest that consideration be given for the use of active agents, suchas serotonin 5-HT_(2A)-receptor modulators, for the treatment of anserotonin 5-HT_(2A)-receptor associated disease or disorder in companionanimals (e.g., cats and dogs) and in livestock animals (e.g., such ascows, chickens, fish, etc). Those of ordinary skill in the art arereadily credited with understanding the utility of such compounds insuch settings.

The formulations prepared by the methods described herein are useful forthe synthesis of any disease or condition for which the administrationof a serotonin 5-HT_(2A)-receptor modulator is indicated.

Pharmacodynamic Effects of the Selective 5-HT_(2A) Inverse Agonist1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea(APD125) in Healthy Adults

APD125, a potent and selective 5-HT_(2A) serotonin receptor inverseagonist is a member of the genus disclosed in the European PatentEP1558582. In Phase 1 trials, APD125 showed vigilance-lowering effectson waking EEG, with maximal effects at 40-80 mg; peak effects wereobserved at 2-4 h after dosing. In the afternoon nap model of insomniain normal volunteers, APD125 increased slow wave sleep and associatedparameters in a dose-dependent manner, primarily during the early partof sleep. These effects occurred at the expense of REM sleep. Sleeponset latency was not decreased by APD125. In the afternoon nap model,APD125 decreased microarousals, the number of sleep stage shifts andnumber of awakenings after sleep onset.

In a Phase 2 trial, when compared to placebo, patients treated withAPD125 experienced statistically significant improvements inmeasurements of sleep maintenance, or the ability to maintain sleepduring the night after falling asleep. The improvements in measurementsof sleep maintenance were achieved without any limiting next daycognitive effects. The data from the APD125 Phase 2 study are consistentwith Phase 1 data and support further development of APD125 for thetreatment of insomnia patients who have difficulty maintaining sleep.

In conclusion, APD125, a 5-HT_(2A) serotonin receptor inverse agonist,improved parameters of sleep consolidation and maintenance in humans.

The invention will be described in greater detail by way of specificexamples. The following examples are offered for illustrative purposes,and are not intended to limit the invention in any manner. Those ofskill in the art will readily recognize a variety of noncriticalparameters which can be changed or modified to yield essentially thesame results.

EXAMPLES Example 1: Pharmacokinetic Experiments General ExperimentalDescriptions:

Male cynomolgus monkeys were administered an oral dose of APD125 incombination with excipients delivered as either a liquid in SGC(composition: 10 mg APD125 in Cremophor®:Labrasol® [1:1]), aswet-granulated tablets (see Example 2) or as dry-granulated tablets (seeExample 7). APD125 dose levels were 10 mg, 30 mg, or 40 mg and themonkeys received approximately 10 mL of tap water after doseadministration. Animals were fasted prior to dosing. Three to sixmonkeys were dosed per treatment group. In two cases, a 2×6 crossoverstudy design was employed. Blood samples were collected via venouspuncture at pre-dose (t=0) and 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h,12 h, 24 h and 48 h post-dose. Blood was treated with an anticoagulantand plasma was separated by centrifugation. Plasma samples were frozenand stored at or below −20° C. prior to analysis.

Pharmacokinetic Data Analysis:

Noncompartmental PK analysis was performed with a commercial softwarepackage (WinNonlin® Professional, version 5.2., Pharsight, MountainView, Calif.; Computer System Validation report CSV-004-SM-R1), withcalculation of the following parameters:

Parameter Definition t_(max) Time of maximum observed plasmaconcentration C_(max) Plasma concentration corresponding to t_(max)AUC_(0-∞) Area under the plasma concentration versus time curve from thetime of dosing to extrapolated to infinity

Bioanalytical Method:

Anticoagulated male cynomolgus monkey plasma samples were analyzed forAPD125 and the internal standard using a selective liquidchromatography-tandem mass spectrometry (LC/MS/MS) method. Plasmaproteins were removed with the addition of acetonitrile at two-fold thetissue volume, followed by centrifugation. The supernatant was injectedonto an HPLC system equipped with a SCIEX API 3000 mass spectrometer.Peak areas were measured against the internal standard in the positiveion MRM mode. Quantitation was performed with regression analyses of theexternal calibration standards.

Example 1.1: Preliminary Wet Granulation-Based Tablet Formulation:Monkey APD125 Plasma Exposure

Monkey APD125 plasma exposure after oral administration of SGCs or wetgranulation tablets are shown in FIG. 1. PK parameters are presented inTable 1. APD125 absorption into the systemic circulation occurred over a2-h to 4-h period followed by a mono-exponential terminal phase. Thetime to maximal plasma concentration (t_(max)) was most rapid for theliquid filled SGCs at 2 h. The t_(max) increased with tabletadministration to 2.7 h and 4 h, for APD125 Form II and APD125 Form I,respectively. The SGC C_(max) (0.953 μg/mL±0.180 μg/mL; dose adjusted to30 mg) was 19-fold and 2-fold greater than the C_(max) for APD125 FormII (0.051 μg/mL±0.007 μg/mL) and APD125 Form I (0.504 μg/mL±0.109μg/mL). The integrated plasma exposures (AUC_(0-∞)) were highest for SGC(4.540 h·μg/mL±1.394 h·μg/mL; dose adjusted to 30 mg) and APD125 Form Itablets (4.998 h·μg/mL±1.739 h·μg/mL). APD125 Form II tablet exposure(0.727 h·μg/mL±0.362 h·μg/mL) was at least 6-fold lower compared to SGCand APD125 Form I tablets.

TABLE 1 Cmax AUC_(0-∞) Dose (μg/mL) (h · μg/mL) Formulation (mg) N MeanSD Mean SD APD125 Form I:PVP (1:8) 10 6 0.227 0.153 1.507 1.218 APD125Form I:PVP (1:8) 30 3 0.504 0.109 4.998 1.739 APD125 Form II:PVP 30 30.051 0.007 0.727 0.362 (1:8) SGC: 10 6 0.942 0.303 3.192 1.291 APD125in [1:1] 30^(a) 2 0.953 0.180 4.540 1.394 Cremophor ®:Labrasol ® 40 21.270 0.240 6.054 1.859 ^(a)40-mg SGC dose adjusted to 30 mg forcomparison purposes.APD125 Form II-based tablets exhibited poor exposure (C_(max) andAUC_(0-∞)) relative to SGCs and therefore, were removed from furtherconsideration. In contrast, APD125 Form I-based tablets exhibitedsimilar integrated exposures (AUC_(0-∞)) to SGCs, with approximatelyhalf the C_(max) of the SGCs, a not uncommon finding when comparingliquid and solid-based formulations. It should be noted, however, thatat a lower dose there was disparity between all exposure parameters. Ata 10-mg dose, SGC C_(max) and AUC_(0-∞) values were four-fold andtwo-fold higher, respectively, compared to the wet granulation tabletexposure parameters suggesting tablets and SGC become dissimilar withdecreasing dose (FIG. 2, FIG. 3, Table 2).

TABLE 2 Cmax(μg/mL) AUC_(0-∞)(h · μg/mL) Formulation Dose (mg) Mean SDMean SD Form I tablet 10 0.227 0.153 1.507 1.218 30 0.504 0.109 4.9981.739 SGC 10 0.942 0.303 3.192 1.291 40 1.270 0.240 6.054 1.859

Example 2: Wet-Granulation Tablet Example 2.1: Tablet Manufacturing

Using a 1-L bowl of high-shear granulator, PVP, APD125, mannitol, methylcellulose, half of the xPVP, and half of the SLS were added to the keyhigh shear granulator. The resulting mixture was dry-mixed for 5 minuteswith impeller and chopper running. After which, water was added slowlyusing a transfer pipette through the addition port on the lid of thegranulator bowl, while the impeller and chopper were still running. Theprocess was stopped once power consumption started to rise quickly. Thelid was then opened, and the granulation visually and texturallyinspected to ensure proper moisture content had been achieved. The wetgranulation was spread evenly over tray paper and dried in an oven at55° C., until a loss on drying (LOD) of less than 5% w/w was achieved.Next, the dried granulation was passed through a mill with round-holescreen size of 0.063″. A 1-qt. blender was charged with this screenedmaterial, and the other half of the SLS and xPVP was added, followed byblending for 5 minutes. Finally, magnesium stearate was added and themixture was blended for 1 minute. Tableting was performed as follows:For each tablet (30 mg), 600 mg final blend was dispensed onto weighpaper and filled into dies (0.730″×0.365″). The granulation was thenpressed into tablets using a carver press to achieve a hardness of about11 kp. General tablet composition is provided in Table 3.

TABLE 3 Ingredient % (w/w) APD125 Form I or Form II (micronized)^(a) 5.0PVP K-29/32 40.0 Mannitol powdered 22.0 xPVP 30.0 Methyl cellulose 0.5SLS 2.0 Magnesium stearate 0.5 Total 100.0 ^(a)For placebo APD125 wasreplaced with mannitol

Example 2.2: Stability Testing

Wet-granulation based placebo, 30-mg Form I, and 30-mg Form II tabletswere placed on stability at 25° C./60% RH and 40° C./75% RH, using 60-mLHDPE bottles (non-induction sealed). Appearance, Assay, DFA,Dissolution, Water Content by Karl Fischer (except at Initial), TabletHardness, Related Substances, and Powder X-ray Diffraction (PXRD)testing were performed at initial (t=0), and at 1-month, 3-month and6-month time points. Results for the wet-granulation Form I and Form IIbased tablets are provided in Table 4. Form I and Form II based tabletinitial, 1-month, 3-month and 6-month dissolution results are providedin Table 5. Three-month and 6-month DFA results are provided in Table 6.Results of the water content determination by Karl Fischer at 1-month,3-month and 6-month time points are provided in Table 7. Initial (t=0),1-month, 3-month and 6-month tablet hardness results are provided inTable 8, while initial (t=0), 1-month, 3-month and 6-month PXRD resultsare provided in Table 9. PXRD results obtained at the 3-month time pointare provided in FIG. 4 and FIG. 5.

TABLE 4 % Assay (% RSD) n = 2 Formulation Conditions t = 0 1 month 3month 6 month Form I 25° C./ 100.3 108.2 101.8 89.8 tablet 60% RH (0.4)(2.4) (1.8) (0.2) 40° C./ 106.9 99.1 84.3 75% RH (5.4) (0.5) (2.6) FormII 25° C./ 97.7 96.8 101.3 91.1 tablet 60% RH (3.4) (0.1) (2.5) (2.3)40° C./ 96.9 99.3 84.3 75% RH (0.7) (1.2) (3.0)

TABLE 5 Formu- Storage Dissolution % Released (% RSD lation Conditions15 min 30 min 45 min 60 min Form I Initial 68.3 79.7 81.6 82.9 tablet(3.7) (0.8) (0.7) (0.4) 1 month at 73.9 85.9 88.4 89.9 25° C./60% RH(3.8) (0.2) (0.8) (0.6) 1 month at 70.3 84.9 88.1 89.6 40° C./75% RH(11.8) (3.1) (1.7) (1.8) 3 months at 76.8 87.6 90.2 91.3 25° C./60% RH(3.2) (1.1) (1.3) (1.3) 3 months at 71.1 85.8 89.1 90.6 40° C./75% RH(8.2) (0.8) (0.4) (0.7) 6 months at 77.0 82.2 86.1 85.1 25° C./60% RH(3.8) (0.7) (0.3) (1.5) 6 months at 65.7 73.5 74.4 75.0 40° C./75% RH(3.1) (1.2) (3.7) (2.7) Form II Initial 47.5 55.9 57.8 58.4 tablet (4.9)(0.5) (0.7) (0.5) 1 month at 48.1 58.3 60.7 61.8 25° C./60% RH (12.5)(1.5) (1.3) (0.6) 1 month at 49.1 57.5 60.0 61.0 40° C./75% RH (5.9)(1.3) (1.0) (0.4) 3 months at 54.1 60.4 62.3 63.4 25° C./60% RH (4.5)(0.4) (0.3) (0.3) 3 months at 54.5 59.8 61.7 63.8 40° C./75% RH (2.9)(1.1) (0.7) (4.3) 6 months at 41.4 48.1 48.1 48.0 25° C./60% RH (3.3)(3.6) (1.1) (0.8) 6 months at 46.4 48.7 49.7 50.9 40° C./75% RH (0.0)(2.2) (0.8) (0.8)

TABLE 6 DFA (ppm) post DFA (ppm) post DFA (ppm) 6 DFA (ppm) 6 3 monthsat 25°/ 3 months at 40°/ months at 25° C./ months at 40° C./ 60% RH n =2 75% RH n = 2 60% RH n = 75% RH n = 2 Formulation (rep1/rep2)(rep1/rep2) 2 (rep1/rep2) (rep1/rep2) Form I tablet ND 165/166 <35833/834 Form II tablet ND 253/245 <35 1400/1414 SGC 542 (est)^(a)4387(est.)^(a) ND ND ^(a)The 3-month SGC results estimated using threetimes mean 28 day data (APD125 5-mg and 40-mgSGC capsule results 189.3ppm and 172.3 ppm at 25° C./60% RH, respectively, and 1658.2 ppm and1266.5 ppm at 40° C./75% RH, respectively). ND = not determined

TABLE 7 % H₂O (rep1/rep2)^(a) Storage 1 month 3 months 6 monthsFormulation Conditions n = 1 n = 2 n = 2 Placebo 25° C./60% RH 7.599.55/9.43 9.36/9.18 40° C./75% RH 8.96 10.50/10.53 10.51/11.15 Form Itablet 25° C./60% RH 8.68 8.32/8.55 8.92/9.24 40° C./75% RH 9.5610.05/9.82 11.93/12.04 Form II tablet 25° C./60% RH 8.75 8.67/8.779.40/9.22 40° C./75% RH 8.86 10.91/10.69 13.35/13.46 ^(a)Water Contentby Karl Fischer was not performed at t = 0

TABLE 8 Target Hard- ness Average Hardness and Range (kp) (kp) n = 4Condition Material t = 0 1 month 3 months 6 months 25° C. Form I/PVP11.0 7.2 7.8 4.8 60% RH (1:8) Wet (4.6-10.1) (3.9-10.1) (3.8-7.0)granulation Form II/PVP 11.0 6.4 7.8 9.4 (1:8) Wet (4.5-9.4) (5.6-12.4)(8.2-12.1) granulation Placebo 10.0 12.9 11.0 11.5 (9.0-21.2) (7.7-14.4)(7.6-16.2) 40° C. Form I/PVP 11.0 5.5 5.9 9.3 75% RH (1:8) Wet (3.5-7.3)(3.9-9.9) (7.8-11.1) granulation Form II/PVP 11.0 7.6 6.8 22.2 (1:8) Wet(6.0-10.0) (4.3-8.0) (23.1-23.6) granulation Placebo 10.0 8.7 9.9 14.9(7.4-10.6) (6.5-14.8) (12.6-13.5)

TABLE 9 APD125 Polymorphic Form(s) Detected Condition Material t = 0 1month 3 months 6 months 25° C. Form I/PVP Form I Form I Form I Form I60% RH (1:8) Wet granulation Form II/PVP Form II Form II Form II —^(b)(1:8) Wet granulation Placebo NA NA NA NA 40° C. Form I/PVP Form I FormI Form I Form I^(a) 75% RH (1:8) Wet granulation Form II/PVP Form IIForm II Form II —^(b) (1:8)Wet granulation Placebo NA NA NA NA ^(a)Somereduction in Form I peak intensity was observed, but no Form II wasdetected. ^(b)PXRD measurements were not collected for the Form IItablets at 6 months. NA = not applicable

The Form I and Form II based wet-granulation tablets exhibited similarchemical stability (Table 4), although it was not possible to accuratelydetermine if a significant drop in assay was occurring for either tabletformulation, due, in part, to the significant assay variation observed.For example, both formulations showed near 100% assay at t=0, but theForm I tablets showed 106.9% assay and 108.2% assay at 1 month, at 40°C./75% RH and 25° C./60% RH, respectively. In addition, since watercontent determination was not added to the stability testing protocoluntil the 1-month time point, none of the assay results were correctedfor water content. This is a significant point, since water contentsincreased from 9.56% w/w to 11.99% w/w at 40° C./75% RH for the Form Ibased tablets (Table 7). Therefore, assay results were only used toconsider the relative stability of Form I and Form II based tablets.Chemical stability of the tablet, relative to SGCs, was evaluated on thebasis of DFA formation rates. For both tablet formulations, low DFAformation rates (Table 6) were observed over the course of the R&Dstability study, far superior to SGCs. Dissolution (Table 5) resultsshowed no significant changes as a function of time, with Form IItablets exhibiting consistently slower dissolution relative to Form Itablets, in agreement with monkey plasma exposure results, supra. Tablethardness measurements (Table 8), on the other hand, showed significantvariability. However, since the tablets were hand pressed rather thanpressed using automated equipment, the wet granulation based tablet R&Dstability hardness results might not be indicative of long-term tablethardness stability. Water content determination by Karl Fischer at1-month and 3-months (Table 7) suggests a possible water uptake of about3% w/w to about 5% w/w between 1 month and 6 months at 40° C./75% RH,suggesting some level of moisture control would be advisable for futuretablet development. PXRD results (Table 9, FIG. 4 and FIG. 5) showedgood solid-state form control, supporting the potential use ofmetastable Form I for further tablet development. However, the Form Itablet 6-month PXRD results at 40° C./75% RH showed some loss in Form Ipeak intensity. The water content of the Form I tablets at 6 months and40° C./75% RH was 11.99% w/w (Table 7), as compared to 9.94% w/w waterat 3 months and 40° C./75% RH and 9.08% w/w water at 6 months and 25°C./60% RH, both of which did not show a loss in Form I content,suggesting water contents of 12% w/w or higher might result in Form Icontent reduction. Therefore, these results suggest future Form I tabletdevelopment should focus upon dry rather than wet-based formulations,and efforts to minimize water uptake, such as utilizing a water barriertablet coating, should be considered. In addition, the 0.5% w/w methylcellulose loading used in the wet-granulation tablets was based uponForm I API stabilization results (see Example 5).

Example 3: Thermal Activity Monitoring MicroWatt Excipient CompatibilityScreening Test Blend Preparation:

Materials for each of the nine formulations shown in Tables 10 through18 were dispensed into separately labeled 60 mL glass jars and manuallyblended (tumbled) for about 5 min.

TABLE 10 Blend 1: APD125/PVP (1:8) Ingredient % (w/w) Amount (g) APD1255.0 0.50 Mannitol (powdered) 21.5 2.15 PVP 40.0 4.00 xPVP 30.0 3.00Methyl cellulose 0.5 0.05 SLS 2.0 0.20 Magnesium stearate 1.0 0.10 Total100.0 10.00

TABLE 11 Blend 2: APD125/PVP (1:5) Ingredient % (w/w) Amount (g) APD1255.0 0.50 Mannitol (powdered) 55.0 5.50 PVP 25.0 2.50 xPVP 12.0 1.20 SLS2.0 0.20 Magnesium stearate 1.0 0.10 Total 100.0 10.00

TABLE 12 Blend 3: APD125/PVP (1:8) Dical phosphate/MCC Ingredient %(w/w) Amount (g) APD125 5.0 0.50 Dical phosphate 20.0 2.00 MCC 20.0 2.00PVP 40.0 4.00 xPVP 11.5 1.15 Methyl cellulose 0.5 0.05 SLS 2.0 0.20Magnesium stearate 1.0 0.10 Total 100.0 10.00

TABLE 13 Blend 4: APD125/PVP (1:8) Mannitol/MCC Ingredient % (w/w)Amount (g) APD125 5.0 0.50 Mannitol (powdered) 20.0 2.00 MCC 20.0 2.00PVP 40.0 4.00 xPVP 11.5 1.15 Methyl cellulose 0.5 0.05 SLS 2.0 0.20Magnesium stearate 1.0 0.10 Total 100.0 10.00

TABLE 14 Blend 5: APD125/coPVP (1:8) Ingredient % (w/w) Amount (g)APD125 5.0 0.50 Mannitol (powdered) 21.5 2.15 coPVP 40.0 4.00 xPVP 30.03.00 Methyl cellulose 0.5 0.05 SLS 2.0 0.20 Magnesium stearate 1.0 0.10Total 100.0 10.00

TABLE 15 Blend 6: APD125/coPVP (1:8) xCMC Ingredient % (w/w) Amount (g)APD125 5.0 0.50 Mannitol (powdered) 21.5 2.15 coPVP 40.0 4.00 xCMC 30.03.00 Methyl cellulose 0.5 0.05 SLS 2.0 0.20 Magnesium stearate 1.0 0.10Total 100.0 10.00

TABLE 16 Blend 7: APD125/PVP (1:8) Dical phosphate/MCC, xCMC Ingredient% (w/w) Amount (g) APD125 5.0 0.50 Dical phosphate 20.0 2.00 MCC 20.02.00 PVP 40.0 4.00 xCMC 11.5 1.15 Methyl cellulose 0.5 0.05 SLS 2.0 0.20Magnesium stearate 1.0 0.10 Total 100.0 10.00

TABLE 17 Blend 8: APD125/PVP (1:5) Dical phosphate/MCC without methylcellulose Ingredient % (w/w) Amount (g) APD125 5.0 0.50 Dical phosphate27.5 2.75 MCC 27.5 2.75 PVP 25.0 2.50 xPVP 12.0 1.20 SLS 2.0 0.20Magnesium stearate 1.0 0.10 Total 100.0 10.00

TABLE 18 Blend 9: APD125/PVP (1:8) Poloxamer Ingredient % (w/w) Amount(g) APD125 5.0 0.50 Mannitol (powdered 21.5 2.15 PVP 40.0 4.00 xPVP 30.03.00 Methyl cellulose 0.5 0.05 Poloxamer 2.0 0.20 Magnesium stearate 1.00.10 Total 100.0 10.00

Experimental Method:

The formulation screening studies were performed at Aptuit Inc., KansasCity, Mo. 64137. Measurements were performed at 40° C. using a thermalactivity monitoring (TAM) model 2277 consisting of four calorimetricunits (2277-201) and standard amplifiers. All data were collected usingDigitam® for Windows, version 4.1, software. Prior to initiating theseries of experiments, each calorimeter unit was calibrated at 100 μWusing a static electrical calibration procedure. Samples of APD125,APD125 formulation blend, or formulation blend placebo were weighed intoseparate 5-mL stainless steel ampoules. Approximately 100 mg of eachmaterial was used. The reference ampoules were loaded with approximately150 mg of 4-mm borosilicate glass balls. Each ampoule was loaded onto anampoule lifter and placed into the equilibrium position. After aninitial pause, a baseline heat flow was recorded prior to lowering thesamples into the measurement position. After sufficient data had beencollected, the ampoules were returned to the equilibrium position and afinal baseline heat flow was collected. The raw heat flow data werebaseline corrected and exported for further data analysis.

Results:

The results for the nine APD125 formulation blends are provided in Table19. The desired result is zero net heat flow, with results within about2 μW/g of zero being indistinguishable from baseline noise. With thesefacts in mind, it can be seen that formulation blends 1, 4, 8 and 9 arethe most compatible blends, while blend 7 is the least compatible.

TABLE 19 Formulation Net Heat Flow Blend Output (μW/g)  1^(a) 0.87 2−13.63 3 8.88  4^(a) −0.23 5 −13.10 6 −8.92 7 −62.36  8^(a) −0.78  9^(a)−1.19 ^(a)Most stable formulation blends

These results suggest that mannitol (diluent/filler), PVP (dispersingagent), xPVP (dispersing agent), methyl cellulose (APD125 Form Istabilizer), poloxamer (wetting agent), magnesium stearate (lubricant),dical phosphate (diluent/filler), MCC (diluent/filler) and SLS (wettingagent), the excipients used in one or more of the four most stableblends (i.e., blends 1, 4, 8 and 9), are suitable for furtherconsideration as excipients. The remaining two excipients used in thestudy, xCMC and coPVP, were not in any of the most stable formulations,and therefore, should be considered to be potentially problematic.

Example 4: Effect of Milling and Compression Upon APD125 Form I SamplePreparation:

Micronized APD125 Form I, was ground using a mortar and pestle, withsamples withdrawn at 1-min, 5-min and 10-min time points for PXRDanalyses to evaluate the impact of grinding upon the solid-state form ofAPD125 Form I. PXRD patterns were obtained pre- and post-milling.Additionally, micronized APD125 Form I, was compressed at 2 kp, 5 kp and10 kp for 1 min per sample using a Carver press. The samples were thenremoved from the Carver press and lightly broken up using a mortar andpestle, prior to PXRD analysis to evaluate the impact of compressionupon the solid-state form of APD125 Form I. PXRD patterns were obtainedpre- and post-compression.

Powder X-Ray Diffraction:

PXRD measurements were obtained using a Philips (PANalytical) X'Pert PROtheta/theta diffractometer (EQ 0233) equipped with an X'Celerator RTMSdetector and utilizing copper Kα radiation, operating at 45 kV and 40mA. The instrument radius was 239.5 mm, the mask filter was 20 mm, thesoller slit was 0.04 radians, and a nickel filter and sample spinningwere used during data acquisition. The application and instrumentcontrol software used were X'Pert Data Collector®, version 2.0c andXPERT-PRO®, version 1.6, respectively. The samples were scanned from 5°to 40° 2θ in continuous mode, using a step size of 0.0167° 2θ.

Results:

In FIG. 6, an overlay of PXRD patterns for micronized APD125 Form I,before and after grinding with a mortar and pestle for 1 minute, 5minutes and 10 minutes are compared. No significant changes in the PXRDpatterns were observed, suggesting that Form I is stable togrinding/milling forces. In FIG. 7, PXRD patterns of APD125 Form Icompressed at 2 kp, 5 kp and 10 kp are compared, with uncompressed FormI. All of the PXRD patterns are consistent with APD125 Form I, althoughwith the possibility of a slight reduction in crystallinity, assuggested by peak broadening and a loss of peak resolution/intensity forthe compressed samples, relative to the uncompressed control sample.

Example 5: Methyl Cellulose Optimization Example 5.1: Test BlendPreparation Example 5.1.1: Form I API Slurries in Water

In a small scintillation vial, 152.13 mg of micronized APD125 Form I,was spiked with sufficient deionized water to make a paste; the weightof the water added, 844.60 mg, was recorded, and the resulting mixturewas stirred using a spatula to obtain a paste. The resulting sample,post-collection of an initial PXRD pattern, was capped, wrapped intinfoil and stored at 40° C. until the next day, when a second PXRDpattern was obtained.

Using another small scintillation vial, 2.1183 g of micronized APD125Form I, was mixed with 3.3619 g of a 0.5% w/v methyl cellulose to obtaina paste, which was immediately sampled for PXRD analysis to verifystarting APD125 solid-state form, post-methyl cellulose addition. Theremaining sample in the scintillation vial was split into two portions,placed in capped, parafilm-wrapped scintillation vials, which were thenwrapped in tinfoil and stored at 40° C. and room temperature,respectively. PXRD patterns were collected at initial (t=0), 2-day and16-day time points for each sample.

Example 5.1.2: Tablet Granulation Slurries in Water

APD125 micronized Form I/PVP (1:8) blend, weighing 3.0081 g andcontaining 0.5% w/w methyl cellulose, was mixed with 3.71277 g of waterto form a paste. After sampling the paste for an initial PXRD pattern,the remaining paste was split into two portions, placed in capped,parafilm-wrapped scintillation vials, which were then wrapped in tinfoiland stored at 40° C. and room temperature, respectively. PXRD patternswere collected at initial (t=0), 1-day, 7-day and 21-day time points.

Example 5.1.3: Tablets (10 mg) Prepared Using 0% w/w, 2% w/w, 5% w/w and8% w/w Methyl Cellulose

For each blend, materials were dispensed (minus magnesium stearate) intoa glass vial and blended for about 5 minutes. Magnesium stearate wasadded and the mixture was blended an additional 2 minutes. The finalblend was compacted into standard round concave tablets ( 5/16″diameter) with a total tablet weight of 200 mg and hardness of 10 kpusing a Carver press. For each batch of tablets, several were crushedusing a mortar and pestle to obtain a fine powder, from which a smallsample was taken for PXRD analysis to confirm the initial APD125polymorphic form. The remaining powder was weighed into a Qorpak®bottle, and ca. 50% w/w deionized water was added. The resulting mixturewas stirred using a micro-spatula to wet the powder and form a paste. ATeflon® lid was screwed on tightly, and the prepared samples were storedin a 40° C. oven. Ground tablet and water weights for each methylcellulose loading are provided in Table 20. PXRD patterns were collectedfor the five tablet granulation/water blends, according to the scheduleprovided in Table 21.

TABLE 20 Weight of Weight of Formulation Used Powder (g) Water (g)APD125:PVP (1:8) 1.4767 1.4802 2% methyl cellulose APD125:PVP (1:8)1.3173 1.5822 5% methyl cellulose APD125:CoPVP (1:8) 1.5436 1.5172 5%methyl cellulose APD125:PVP (1:8) 8% 1.5355 1.5049 methyl celluloseAPD125:PVP (1:8) 1.64810 1.63835

TABLE 21 XRD Results Suggest Formulation Used Time Point Major Presenceof: 2% methyl cellulose Initial (no water) Form I 1 day Form I 1 weekForm II 4 weeks — 5% methyl cellulose, Initial (no water) Form I PVP 1day Form I 1 week Form I 4 weeks Form I 5% methyl cellulose, Initial (nowater) Form I coPVP 1 day Form I 1 week Form I 4 weeks Form II 8% methylcellulose Initial (no water) Form I 1 day Form I 1 week Form I 4 weeksForm I and Form II 0% methyl cellulose Initial (no water) Form I 1 dayForm II 1 week — 4 weeks —

Example 5.2: Powder X-Ray Diffraction

PXRD measurements were obtained using a Philips (PANalytical) X'Pert PROtheta/theta diffractometer (EQ 0233) equipped with an X'Celerator RTMSdetector and utilizing copper Kα radiation, operating at 45 kV and 40mA. The instrument radius was 239.5 mm, the mask filter was 20 mm, thesoller slit was 0.04 radians, and a nickel filter and sample spinningwere used during data acquisition. The application and instrumentcontrol software used were X'Pert Data Collector®, version 2.0c andXPERT-PRO®, version 1.6, respectively. The API-based paste samples werescanned from 5° to 40° 2θ in continuous mode, using a step size of0.0167° 2θ and a counting time of 40.005 seconds. The tablet granulationsamples were scanned from 2° to 15° 2θ in continuous mode, using a stepsize of 0.0167° 2θ and a counting time of 1063.625 s.

An aqueous 0.5% w/w methyl cellulose solution of Form I at 40° C. showedno evidence of conversion to Form II after 16 days (FIG. 8), in sharpcontract to a Form I paste in water alone at 40° C., which converted toForm II within 24 hours (FIG. 9). As a result, 0.5% w/w methyl cellulosewas added to the first APD125 wet-granulation tablet to hinder theconversion of Form I to Form II. However, the effectiveness of methylcellulose in a tablet matrix has not been previously investigated.Therefore, as a first step, the wet-granulation tablet blend, containing0.5% w/w methyl cellulose, was mixed with 50% w/w water to form a pasteand stored at room temperature and 40° C. to determine if conversion toForm II was inhibited. Initial (t=0) and 24 hour PXRD patterns for thewet samples are shown in FIG. 10. After 24 hours, the sample stored at40° C. showed conversion to Form II; while the room-temperature samplewas still Form I. As shown in FIG. 11, the room-temperature sampleremains Form I at 7 days, finally converting to Form II at 21 days.

In contrast to pure APD125 Form I suspended in aqueous 0.5% w/w methylcellulose, which did not convert to Form II in 21 days at roomtemperature, the tablet did show conversion to Form II. Therefore, itwas decided to evaluate higher methyl cellulose concentrations todetermine if conversion to Form II could be more effectively inhibited.PVP-based direct compression tablets were prepared containing 0% w/w, 2%w/w, 5% w/w and 8% w/w methyl cellulose. In addition, coPVP-based directcompression tablets were prepared containing 5% w/w methyl cellulose. Ineach case, the tablets were ground, mixed with 50% w/w water and storedat 40° C., with PXRD patterns collected at t=0, 24 h, 1 week and 4 weeks(1 month). As shown in FIG. 12, all samples contained Form I initially,but by 24 hours (FIG. 13), the sample without methyl cellulose showedconversion to Form II, as was previously observed for the 0.5% w/wmethyl cellulose tablet blend.

After 1 week at 40° C., the 2% w/w methyl cellulose sample showedconversion to Form II (FIG. 14), while the remaining samples, containing5% w/w and 8% w/w methyl cellulose, started to show conversion to FormII at 1 month (FIG. 15). Thus, 2% w/w, 5% w/w and 8% w/w methylcellulose containing tablets showed retarded conversion to Form IIrelative to the 0% w/w methyl cellulose control and the previouslystudied 0.5% w/w methyl cellulose containing tablet.

In addition to maintaining Form I, a primary goal of APD125 tabletformulation development is to minimize DFA formation. As can be seen inTable 25, although methyl cellulose loadings of 5% w/w and 8% w/wexhibited the best inhibition of Form II, they also resulted inincreased DFA formation, relative to the 0% w/w methyl cellulosecontrol. In addition, at the 5% w/w methyl cellulose loading, thecoPVP-based tablets showed over three times the DFA formation of thePVP-based tablets, suggesting, as in the case of the TAM results, thatcoPVP might be less desirable as an excipient than PVP. The 2% w/wmethyl cellulose loading provided the best overall balance of optimalchemical stability, while retaining a reasonable ability to inhibit theformation of Form II (FIG. 13, Table 25), and therefore, was used as thebasis of further tablet development.

Example 5.3: DFA Assay

In addition to maintaining Form I, a primary goal of APD125 tabletformulation development was to minimize DFA formation. The 4-week 40°C./75% RH samples were pulled from their stability chambers and allowedto dry over the course of a couple of days under nitrogen. The materialwas then broken up using a micro-spatula until enough material wasavailable for the DFA HPLC analysis. The samples were allowed to sit insolution for 4 hours before being filtered by centrifugation andtransferred into an HPLC vial for analysis. Manual integration was usedfor all chromatograms.

As can be seen in Table 22, although methyl cellulose loadings of 5% w/wand 8% w/w exhibited the best inhibition of Form II, they also resultedin increased DFA formation, relative to the 0% w/w methyl cellulosecontrol. In addition, at the 5% w/w methyl cellulose loading, thecoPVP-based tablets showed over three times the DFA formation of thePVP-based tablets, suggesting, as in the case of the TAM results, thatcoPVP might be less desirable as an excipient than PVP. The 2% w/wmethyl cellulose loading provided the best overall balance of optimalchemical stability, while retaining a reasonable ability to inhibit theformation of Form II (FIG. 13, Table 22), and therefore, was used as thebasis of further tablet development.

TABLE 22 Form Detected DFA (n = 1) Formulation (1 day) (1 week) (4weeks) (4 weeks) APD125 Form I/PVP (1:8) Form II Not applicable Notapplicable 37 ppm No methyl cellulose APD125 Form I/PVP (1:8) Form IForm II Not applicable 34 ppm 2% w/w methyl cellulose APD125 Form I/PVP(1:8) Form I Form I Form I 80 ppm 5% w/w methyl cellulose APD125 FormI/coPVP (1:8) Form I Form I Form II 292 ppm  5% w/w methyl celluloseAPD125 Form I/PVP (1:8) Form I Form I Form I/Form II 105 ppm  8% w/wmethyl cellulose mixture

Example 6: PVP/API and coPVP/API Ratio Optimization Example 6.1: SamplePreparation

APD125 Form I and either PVP or coPVP were weighed out and mixed toobtain API/PVP or API/coPVP ratios of 1:1, 1:3, 1:5 and 1:8. Theresulting mixtures were blended for ca. 5 min, screened through a #40screen, and blended for an additional ca. 5 minutes.

Example 6.2: Scanning Electron Microscopy Analysis

Each sample was lightly stirred with a micro-spatula and a small portionof the material was tapped onto double-sided adhesive on a disposablescanning electron microscopy (SEM) stage at a height no greater than 0.5cm. The SEM stage was lightly tapped to remove any loose material thatdid not adhere to the adhesive, and the prepared sample was placed inthe SEM chamber. Images were collected using a FEI Quanta 200 (S/ND7554-R).

The 1:1 blend showed significant amounts of residual APD125 not coatedonto the PVP particles, whereas the 1:3, 1:5 and 1:8 SEM images showedsimilar and significantly less residual APD125, not coated onto PVP,suggesting an API:PVP ratio of greater than 1:1, but no more than 1:3 isrequired to disperse most of the APD125 onto the PVP. APD125 does notuniformly coat the PVP particles, but tends to adhere more thickly tosome areas than others, possibly due to variations in electrostatics.

Similar SEM results were obtained for API/coPVP blends. Once again,based upon the SEM images, it would appear that the least residualAPD125 was observed at API:coPVP ratios of 1:3 or greater.

Example 6.3: Monkey APD125 Plasma Exposure—APD125 Form I:PVP and APD125Form I:coPVP Tablet Formulations

The effects of PVP and coPVP in various ratios with APD125 on APD125plasma exposure in monkeys after oral administration of direct (dry)compression tablets containing 10 mg of APD125 were examined. APD125plasma exposure (AUC_(0-∞)) at APD125:PVP ratios of 1:1, 1:4 and 1:6were similar at 0.548±0.321 h·μg/mL, 0.575±0.379 h·μg/mL and 0.572±0.556h·μg/mL, respectively. At an APD125:PVP ratio of 1:8, however, plasmaexposure (1.262±0.660 h·μg/mL) increased twofold compared to the 1:1,1:4 and 1:6 ratios (FIG. 16, Table 23). The replacement of PVP withcoPVP in the direct compression tablet at a ratio of 1:8 did not affectAPD125 exposure: APD125:PVP, 1.262±0.660 h·μg/mL; APD125:coPVP,1.889±1.162 h·μg/mL (FIG. 20, Table 23). Therefore, the final prototypetablets were 1:8 APD125:PVP or 1:8 APD125:coPVP ratio basedformulations.

TABLE 23 C_(max) AUC_(0-∞) t_(max) Dose (μg/mL) (h · μg/mL) (h)Formulation (mg) N Mean SD Mean SD Mean SD APD125 Form I:PVP (1:1) DC 106 0.077 0.057 0.548 0.321 4.7 2.1 APD125 Form I:PVP (1:4) DC 10 6 0.0850.071 0.575 0.379 4.7 4.3 APD125 Form I:PVP (1:6) DC 10 6 0.125 0.1740.572 0.556 4.3 2.3 APD125 Form I:PVP (1:8) DC 10 3 0.335 0.138 1.2620.660 2.7 0.8 APD125 Form I:coPVP (1:8) DC 10 5 0.471 0.413 1.889 1.1622.4 0.9 APD125 Form I:PVP (1:8) WET 10 6 0.227 0.153 1.507 1.218 2.2 1.0Soft gelatin capsule 10 6 0.942 0.303 3.192 1.291 2.2 1.0

Example 7: Direct Compression Tablet Example 7.1: Micronization ofAPD125 Form I

APD125 Form I (12.5 kg, particle size d₁₀ of 1.75 μm, d₅₀ of 6.98 μm,d₉₀ of 38.45 μm) (Sympatec Helos wet dispersion laser diffractionparticle size analyzer) was micronized in a 300 mm spiral jet mill at asolid feed rate of 20.0 kg/h with a grinding pressure of 6.5±0.5 bar anda filtered nitrogen gas feed pressure of 10±0.5 bar to produce APD125Form I (11.55 kg, 92.4% yield) of 99.93% purity by HPLC peak area. Themicronized product was found to have a particle size d₉₀ of 6.16 m witha Sympatec Helos wet dispersion laser diffraction particle sizeanalyzer.

Example 7.2: Tablet Manufacturing for 5% w/w Methyl Cellulose-LoadedTablets

Materials were dispensed according to the target tablet quantitativecomposition. Micronized APD125, PVP and methyl cellulose were preblendedin a bag, and then hand-screened through a #40-mesh sieve. A 2-qt.blender was charged with the preblend, and all other remaining materialswere added, minus the magnesium stearate, followed by blending for 300rotations (12 min at 25 rpm). Finally, the magnesium stearate was added,and the resulting mixture was blended for an additional 100 rotations (4minutes at 25 rpm). This material was compressed into 200-mg tabletsusing a Piccola PLC tablet press equipped with two stations of 5/16″standard round concave tooling to achieve a target 5-kp to 8-kp tablethardness.

Example 7.3: Tablet Manufacturing for 2% w/w Methyl Cellulose-LoadedTablets

Materials were dispensed according to the target tablet quantitativecomposition. A blender was charged with all of the tablet components,minus magnesium stearate, and blended for 300 rotations (12 min at 25rpm). The resulting blend was delumped using a Comill (equipped with anR045 screen and round-arm impeller), transferred into a blender, andblended for 300 rotations (12 min at 25 rpm). The magnesium stearate wasadded, followed by blending for an additional 100 rotations (4 min at 25rpm). The resulting final blend was compressed into 200-mg tablets(containing 10 mg of micronized APD125 Form I API) to a target hardnessof 5 kp to 8 kp, using a Piccola PLC tablet press, equipped with 5/16″standard round concave tooling. For the 40-mg active tablets, the finalblend was compressed into 800-mg tablets to a target hardness of 12 kpto 16 kp, using 0.730″×0.365″ plain oval tooling. Finally, all tabletcores were film coated with Opadry® II Blue 85F90996 to a 5% weightgain, using a fully perforated 11.5″ pan. Final tablet composition isprovided in Table 24.

TABLE 24 Ingredient % (w/w) Amount (g) Core tablet APD125 (Micronized)5.00 50.0 PVP, Plasdone ™ K-29/32 or coPVP, 40.00 400.0 Kollidon ™ VA 64Lactose monohydrate, 316 21.25 212.5 Microcrystalline cellulose, PH10225.00 250.0 Crospovidone, Kollidon ™ CL 4.00 40.0 Methyl cellulose 2.0020.0 Sodium lauryl sulfate 2.00 20.0 Magnesium stearate 0.50 5.0 Silicondioxide 0.25 2.5 Total 100.00 1000.0 Film coat Opadry ® II Blue 85F909965 NA NA = not applicable

Example 7.4: Monkey APD125 Plasma Exposure

Monkey APD125 exposure studies conducted with wet granulation basedAPD125 Form I 10-mg tablets, containing 0.5% w/w methyl cellulose, wereshown to exhibit roughly one-half the AUC_(0-∞), and one-fourth theC_(max) of SGCs (Example 1.1). Additionally, monkey studies usinguncoated direct compression APD125 Form I 10-mg tablets, containing 5%w/w methyl cellulose found the direct compression tablets to exhibitessentially the same exposure as previously observed for thewet-granulation tablets (Example 6.3). Based on the PK data and themethyl cellulose formulation stability results (Table 22), a decisionwas made to prepare two final, separate R&D batches of coateddirect-compression tablets with 40 mg APD125 Form I, containing methylcellulose at 2% w/w, and either PVP or coPVP.

Six monkeys were dosed in a 2×6 crossover design. APD125 plasma exposureafter oral administration of 40 mg APD125 in SGC or dry compressiontablets are shown in FIG. 18. Pharmacokinetic parameters are presentedin Table 25. APD125 absorption into the systemic circulation occurredover a 3-h period followed by a mono-exponential terminal phase. Thetime to maximal plasma concentration (t_(max)) was most rapid for theliquid filled SGC at 2.2 h. The t_(max) increased with tabletadministration to 3.3 h. The SGC C_(max)(0.850±0.462 μg/mL) wasapproximately twofold greater than the C_(max) for APD125 Form I tablet(0.464±0.236 μg/mL). The integrated plasma exposures (AUC_(0-∞)) for SGCand APD125 Form I tablet were similar (4.395±3.122 h·μg/mL) and APD125Form I (4.223±2.660 h·μg/mL). The extended t_(max), reduced Cmax andsimilar overall exposures (AUC_(0-∞)) of the tablet formulation comparedto the SGC formulation corroborate the exploratory formulationsdiscussed in Example 1.1 (Table 1).

TABLE 25 C_(max) AUC_(0-∞) t_(max) Dose (μg/mL) (h · μg/mL) (h)Formulation (mg) N Mean SD Mean SD Mean SD Tablet APD125 Form I:PVP 40 60.46 0.236 4.223 2.660 3.3 1.0 (1:8) coated direct-compression, 2% w/wmethyl cellulose Soft gelatin capsule 40 6 0.850 0.462 4.395 3.122 2.21.0

As can be seen in Table 25, APD125 Form I:PVP (1:8) coateddirect-compression tablets exhibit essentially identical AUC_(0-∞)results to the SGC at a 40-mg dose, as was expected on the basis of theprevious wet-granulation tablet monkey PK results. Additionally, the40-mg tablets exhibited roughly one-half the Cmax of the SGCs and aslightly longer t_(max), which is also consistent with previous wetgranulation tablet PK results.

Example 7.5: R&D Stability Testing

10-mg and 40-mg, PVP and coPVP-based prototype APD125 tablets wereplaced on stability at 25° C./60% RH and 40° C./75% RH, contained inHDPE bottles with induction seal and desiccant. Appearance, dissolution,water content by Karl Fischer, PXRD, related substances and tablethardness tests were performed at initial and 8-week time points only.Compound II, DFA and related substances were assayed at initial, 2-weekand 4-week time points. Additional tablets were also stored in opencontainers at 40° C./75% RH, pulled and analyzed at the 4-week timepoint for DFA and compound II.

PVP-based and coPVP-based tablet formulations showed comparable overallchemical stability during the 8-week study, with no significant loss inAPD125 observed, as demonstrated by the assay results shown in Table 26.The DFA results for the final two R&D formulations are provided in Table27.

TABLE 26 APD125 % Assay (% RSD) Dose Initial 2 weeks 4 weeks 8 weeksFormulation Conditions (mg) n = 3 n = 3 n = 3 n = 3 APD125 Form I:PVP(1:8) 40° C. 10 90.5 (0.5) 93.0 (0.6) 102.3 (4.9) 93.7 (2.4) 2% w/wmethyl cellulose, 75% RH 40 93.1 (0.5) 91.3 (0.7) 102.3 (3.6) 97.7 (2.1)direct-compression (coated) 25° C. 10 90.5 (0.5) NT NT 95.4 (2.1) 60% RH40 93.1 (0.5) NT NT 96.9 (2.0) APD125 Form I:coPVP (1:8) 40° C. 10 90.4(0.5) 91.8 (1.8) 92.6 (0.9) 95.1 (1.5) 2% w/w methyl cellulose, 75% RH40 92.5 (1.5) 97.5 (5.9) 93.1 (0.9) 97.0 (0.9) direct-compression(coated) 25° C. 10 90.4 (0.5) NT NT 93.3 (1.1) 60% RH 40 92.5 (1.5) NTNT 96.7 (2.7) NT = not tested

TABLE 27 DFA Concentration as ppm (% RSD) Dose Initial 2 weeks 4 weeks 8weeks Formulation Conditions (mg) n = 2 n = 2 n = 2 n = 2 APD125 FormI:PVP (1:8) 40° C. 10 ND^(a) <35 <35 <35 2% w/w methyl cellulose, 75% RH40 ND^(a) <35 <35 <35 direct-compression (coated), 25° C. 10 ND^(a) NANA ND^(a) HDPE bottle with desiccant 60% RH 40 ND^(a) NA NA ND^(a)APD125 Form I:coPVP (1:8) 40° C. 10 ND^(a) 69 (1.8) 114 (1.7) 142 (2.4)2% w/w methyl cellulose, 75% RH 40 ND^(a) 67 (1.2) 145 (0.6) 161 (1.1)direct-compression (coated), 25° C. 10 ND^(a) NA NA ND^(a) HDPE bottlewith desiccant 60% RH 40 ND^(a) NA NA ND^(a) APD125 Form I:PVP (1:8) 40°C. 10 ND^(a) NA 645 (0.2) NA 2% w/w methyl cellulose, 75% RH 40 ND^(a)NA 918 (0.5 NA direct-compression (coated), open container APD125 FormI:coPVP (1:8) 40° C. 10 ND^(a) NA 648 (1.7) NA 2% w/w methyl cellulose,75% RH 40 ND^(a) NA 788 (1.4) NA direct-compression (coated), opencontainer ^(a)DFA limit of detection and limit of quantitation are 10ppm and 35 ppm respectively NA = not applicable ND = Not detected

As was previously observed during the methyl cellulose optimizationstudies (Table 22), the coPVP-based tablets were found to exhibit fasterDFA formation rates than the corresponding PVP-based tablets, which isalso consistent with TAM results (Example 3), suggesting potentialcompatibility issues with coPVP. Interestingly, the open-containerresults (Table 27) show similar DFA formation rates for both PVP-basedand coPVP-based tablets, in contrast with HDPE bottle stability andmethyl cellulose optimization results, which suggested tabletscontaining coPVP exhibit faster DFA formation than PVP-based tablets.This apparent discrepancy might be due to water content differences. Inthe cases of the HDPE bottle stability and methyl cellulose optimizationstudies, the amount of water present in the samples is very similar,which allows one to better assess the impact of changing from PVP tocoPVP. However, in the case of the open-container stability studyresults, each sample would equilibrate to quite different watercontents, as shown in FIG. 20. At a relative humidity of 75%, thePVP-based tablets could be expected to absorb significantly more waterthan the coPVP-based tablets, and since hydrolysis is a major pathwayfor DFA formation, it is not unreasonable that the open containerPVP-based tablets would begin to show faster DFA formation, becomingnearly identical to the open container coPVP-based tablets. It istherefore possible that the observed increased DFA formation rate in thepresence of coPVP, relative to PVP, is not the result of chemicalincompatibility with coPVP. Instead, at a fixed water content in aclosed system, the more hygroscopic PVP, relative to coPVP, might reducethe amount of free water available for hydrolysis of APD125.

As shown in Table 28 and Table 29, both PVP-based and coPVP-basedtablets exhibited no evidence of significant Compound II assay anddissolution rate changes post-8 weeks at 40° C./75% RH, with theexception of the open container results, consistent with the DFAresults, shown in Table 27. The PXRD results show that all samplestested contain Form I, indicating good solid-state form stability forboth PVP-based and coPVP-based tablets (Table 30). The water contentdetermination by Karl Fischer showed essentially no change in watercontent over the 8-week study (Table 31). There was, however, a slightlyhigher water content observed for the PVP-based tablets, relative to thecoPVP-based tablets, which is consistent with the fact that PVP issomewhat more hygroscopic than coPVP (FIG. 19).

TABLE 28 Compound II Concentration as % area (% RSD) Dose Initial 2weeks 4 weeks 8 weeks Formulation Conditions (mg) n = 2 n = 2 n = 2 n =2 APD125 Form I:PVP (1:8) 40° C. 10 ND^(a) ND^(a) ND^(a) <0.05 2% w/wmethyl cellulose, 75% RH 40 ND^(a) ND^(a) ND^(a) <0.05direct-compression (coated), 25° C. 10 ND^(a) NA NA <0.05 HDPE bottlewith desiccant 60% RH 40 ND^(a) NA NA <0.05 APD125 Form I:coPVP (1:8)40° C. 10 ND^(a) ND^(a) ND^(a) <0.05 2% w/w methyl cellulose, 75% RH 40ND^(a) ND^(a) ND^(a) <0.05 direct-compression (coated), 25° C. 10 ND^(a)NA NA <0.05 HDPE bottle with desiccant 60% RH 40 ND^(a) NA NA <0.05APD125 Form I:PVP (1:8) 40° C. 10 ND^(a) NA 0.24 (5.89) NA 2% w/w methylcellulose, 75% RH 40 ND^(a) NA 0.26 (2.77) NA direct-compression(coated), open container APD125 Form I:coPVP (1:8) 40° C. 10 ND^(a) NA0.24 (5.89) NA 2% w/w methyl cellulose, 75% RH 40 ND^(a) NA  0.33(15.23) NA direct-compression (coated), open container

TABLE 29 APD125 % Released at 60 min (% RSD) Dose Initial 8 weeksFormulation Conditions (mg) n = 4 n = 4 APD125 Form I:PVP 40° C. 10103.9 (3.4)  97.0 (3.1) (1:8) 2% w/w methyl 75% RH 40 98.9 (2.5) 95.9(1.4) cellulose, direct- 25° C. 10 103.9 (3.4)  101.0 (1.7)  compression(coated) 60% RH 40 98.9 (2.5) 100.4 (2.0)  APD125 40° C. 10 100.0 (0.7) 95.6 (0.9) Form I:coPVP) 75% RH 40 98.3 (1.3) 94.5 (0.8) (1:8 2% w/wmethyl 25° C. 10 100.0 (0.7)  99.0 (0.9) cellulose, direct- 60% RH 4098.3 (1.3) 98.9 (0.8) compression (coated)

TABLE 30 APD125 Polymorph(s) Dose Detected Formulation Conditions (mg)Initial 8 weeks APD125 Form I:PVP (1:8) 40° C. 10 Form I Form I 2% w/wmethyl cellulose, 75% RH 40 Form I Form I direct-compression (coated)25° C. 10 Form I Form I 60% RH 40 Form I Form I APD125 Form I:coPVP(1:8) 40° C. 10 Form I Form I 2% w/w methyl cellulose, 75% RH 40 Form IForm I direct-compression (coated) 25° C. 10 Form I Form I 60% RH 40Form I Form I

TABLE 31 % water Content (% RSD) Dose Initial 8 weeks FormulationConditions (mg) n = 3 n = 3 APD125 Form I:PVP (1:8) 25° C. 10 6.7 (4.5)4.8 (0.9) 2% w/w methyl cellulose, 60% RH 40 5.7 (3.7) 4.5 (1.1)direct-compression (coated) 40° C. 10 6.7 (4.5) 6.5 (0.0)^(a) 75% RH 405.7 (3.7) 5.7 (5.9)^(a) APD125 Form I:coPVP 25° C. 10 4.7 (5.2) 4.1(19.2) (1:8) 2% w/w methyl 60% RH 40 4.3 (0.8) 3.9 (0.7)^(a) cellulose,direct- 40° C. 10 4.7 (5.2) 4.9 (1.7)^(a) compression (coated) 75% RH 404.3 (0.8) 4.5 (0.8)^(a) ^(a)n = 2

Example 7.6: Nine Months Stability Testing

10-mg and 40-mg, PVP and coPVP-based prototype APD125 tablets wereplaced on stability testing packaged in HDPE bottles 60 cc with andwithout desiccant. See Table 32.

TABLE 32 Batches Tested and Packaging Batch Formulation StrengthPackaging 1 APD125/PVP 10 mg HDPE bottles 2 40 mg with desiccant 3APD125/coPVP 10 mg 4 40 mg 5 APD125/PVP 10 mg HDPE bottles 6 40 mgwithout desiccant 7 APD125/coPVP 10 mg 8 40 mg 9 Placebo/PVP (10 mg)HDPE bottles with desiccant 10 (10 mg) HDPE bottles without desiccant 11(40 mg) HDPE bottles with desiccant 12 (40 mg) HDPE bottles withoutdesiccant

The stability samples were stored at 25° C./60% relative humidity, 30°C./65% relative humidity and 40° C./75% relative humidity to examine theeffect of heat and humidity. The studies are conducted according to ICHQ1A® guidelines (stability testing of new drug substances and products).

After a storage duration of 6 months, the stability tests with tabletsin bottles without desiccant were stopped and only the stability testswith tablets in bottles with desiccant were measured after a storageduration of 9 months.

After a storage duration of 9 months at 25° C./60% relative humidity inbottles with desiccant, the tablets show an increase of the watercontent compared with the initial values (PVP max.+2.4%, coPVP max.+4%,placebo tablets max.+1.6%). The tablets were tested again after 10.5months and the water content was found to be lower than it had been at 9months. The water content at 10.5 months compared with the initialvalues was: PVP max.+0.5%; coPVP max.+0.5%; placebo tablets max.+0.1%).The difference in water content at 9 months and 10.5 months is probablydue to the testing protocols used. At 9 months the tablets were groundon one day but the water content was not measured until the followingday. During this delay it is believed the ground tablets picked upmoisture from the air. At 10.5 months however, the tablets were groundand tested for water content on the same day.

After a storage duration of 9 months at 25° C./60% relative humidity inbottles with desiccant, a decrease of the crushing strength of thetablets was observed compared with the initial values. The decrease ofthe 10 mg tablets was higher than the 40 mg tablets (10 mg max.=−24 N;40 mg max.=−8 N). No significant differences were observed between theactive and the placebo tablets and between the PVP and the coPVPformulation.

After a storage duration of 9 months at 25° C./60% relative humidity inbottles with desiccant, no significant decrease of the dissolution ratecan be observed.

After a storage duration of 9 months at 25° C./60% relative humidity inbottles with desiccant, the assay results for APD125 were in the samerange as the initial conditions. No significant trends of the assayresults can be observed and all results are within the specification.

After a storage duration of 9 months at 25° C./60% relative humidity inbottles with desiccant, small amounts of DFA were detected but allresults were below the quantitation limit of 75 ppm. For otherimpurities, no increase were observed and all results were <0.05%.

Example 8: Preparation of IntermediateN-[4-Methoxy-3-(2-methyl-2H-pyrazol-3-yl) phenyl]-acetamide

To a solution of N-[4-methoxy-3-(2-methyl-2H-pyrazol-3-yl)phenyl]-acetamide (25.0 kg) in N,N-dimethylacetamide (DMA, 140.5 kg) ina 400 L glass lined jacketed reactor with overhead stirring undernitrogen at 45 to 55° C. internal temperature N-bromosuccinimide (NBS,19.0 kg) was charged in portions at such a rate as to maintain internaltemperature to less than 55° C. The reaction mixture remained a solutionat this dilution of DMA and internal temperature of 50.9° C. An “inprocess check” of the reaction mixture to determine reaction completionafter at least 1 hr of stirring at 50° C. showed that the reactionmixture was substantially free of the starting material. Upon cooling ofthe reaction mixture to an internal temperature of 34° C. water (150 kg)was added in a controlled manner into the reactor to maintain aninternal temperature between 40-55° C. A slight exotherm was observedduring the reaction quench. The product slurry was then cooled to −5 to5° C. and filtered through a corrosion resistant filter/dryer. Thewetcake was re-slurried, washed with water (2×25 kg), and dried underfull house vacuum (˜30 in Hg) with a jacket temperature of 65° C.producing N-[3-(4 bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxyphenyl]-acetamide (31.6 kg, 100% purity by HPLC, 96.1% yield).

Example 9: Preparation of Intermediate3-(4-Bromo-2-methyl-2H-methyl-3-yl)-4-methoxy-phenylamine

N-[3-(4 Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy phenyl]-acetamide(15.6 kg), xylenes (67.1 kg), n-propanol (12.5 kg), and sodium hydroxidepellets (4.1 kg) were charged into a 400 L Hastelloy jacketed reactorwith overhead stirring and nitrogen blanket. The reaction mixture washeated and held at reflux for at least four hours with a peak internaltemperature of 107° C. at which point the HPLC analysis of the reactionmixture indicated substantially complete deacetylation of the startingmaterial to product. The reactor condenser was then switched from refluxto distillation configuration to remove most of the n-propanol solvent.This was accomplished by monitoring the temperature profile of thereactor contents and monitoring when the temperature stabilized(126-127° C. T_(internal) with up to 145° C. T_(jacket)) indicatingnear-complete removal of n-propanol. The product mixture was cooled to80° C. and water (15.6 L) was added to extract the inorganic materialfrom the product dissolved in xylenes. The aqueous extraction wasrepeated by adding water (11.7 kg) at 70-80° C. and performing a secondextraction to remove residual inorganics from the product solution. Uponcooling to 65° C. vacuum was applied to effect distillation ofapproximately 40% of initial xylenes charge at which point precipitationwas observed. The reaction slurry was further cooled to 40° C.Cyclohexane (10.5 L) was charged in portions to control precipitation atan internal temperature 36.6 to 41.1° C. Upon completion of thecyclohexane anti-solvent addition, the reaction mixture was cooled to−11.9° C. (maximize the yield). The solid product was filtered using afilter/dryer, washed with cyclohexane (2×12.2 kg), and dried under fullhouse vacuum (˜30 in Hg) and with increasing internal temperature up to40° C. isolating3-(4-bromo-2-methyl-2H-methyl-3-yl)-4-methoxy-phenylamine (12.29 kg,100% purity by HPLC, and 92% yield).

Example 10: Preparation of Form I of1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea,Direct Method, (Compound I)

To a solution of3-(4-bromo-2-methyl-2H-methyl-3-yl)-4-methoxy-phenylamine (16.7 kg) inacetonitrile (78.6 kg) in a 200 L glass jacketed reactor with overheadstirring and nitrogen blanket at an internal temperature of <−10° C.2,4-difluorophenyl-isocyanate (9.68 kg) was controlled charged through a1 micron line filter at a rate substantially slow enough to preventco-precipitation of the starting material in the product. Aftercontinued stirring at <−10° C. for approximately 1 hour post completionof the 2,4-difluorophenyl-isocyanate addition, the conversion ofstarting material to product was substantially complete. The productslurry was filtered and washed with cold acetonitrile (26.3 kg) at <−5°C. producing the acetonitrile solvate of the product. Full house vacuum(˜30 in Hg) was applied to the bottom outlet filter/dryer while nitrogenflowed through from the top enhancing the removal of volatile solventswithout application of heat. Samples were removed from the bulk materialand LOD was determined using an IR-200 Moisture Analyzer Instrument(Denver Instrument Company). The time course is shown below:

Sample No. LOD % Time (h) 1 38.48 0 2 29.63 7 3 20.96 13.5 4 7.28 19.5Drying of the “wetcake” was maintained at ambient temperature under fullhouse vacuum (˜30 in Hg) for about 19.5 h at which time the LOD was7.28%. At this point, the temperature was raised to 70° C. under fullhouse vacuum (˜30 in Hg) for 11 hrs to afford1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea(24.2 kg, 99.94% HPLC purity, form I determined by PXRD, and 92.9%yield).

Example 11: Conversion of Form II of1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureato Form I of1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea

1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea(24.2 kg) was dissolved in tetrahydrofuran (85.6 kg) in a 200 LHastelloy jacketed reactor with overhead stirring and nitrogen blanketat or near reflux (62.4° C.). Solids which had precipitated on the wallwere washed down with THF (8.6 kg). The THF solution was transferredthrough a line filter into a 400 L glass lined reactor. At a reduced THFsolution internal temperature of <−5° C., heptane (128.5 kg) was addedinto the reactor at a controlled rate such that internal temperature didnot exceed −5° C. After having been stirred at <−5° C. for 17 min, theresulting slurry was filtered through a Hastelloy filter/dryer, and thesolid product was washed with precooled acetonitrile (18.9 kg) at −11°C. (without the acetonitrile wash, the heptane level in the driedproduct would be about 10,000 ppm, which would exceed the ICH guidelineof <5000 ppm). Full house vacuum (˜30 in Hg) was applied to the bottomoutlet filter/dryer while nitrogen flows through from the top enhancingthe removal of volatile solvents without application of heat. Thevolatile solvent content of the wetcake was 4.85% prior to applicationof heat. Upon drying at 70° C. under full house vacuum (˜30 in Hg),1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea(21.9 kg, Form I determined by PXRD, and 90.5% yield) was isolated.

Example 12: Powder X-Ray Diffraction of Form I of1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea(Compound I)

Powder X-ray Diffraction (PXRD) data were collected on an X'Pert PRO MPDpowder diffractometer (PANalytical, Inc.) with a Cu source set at 45 kVand 40 mA, a Ni-filter to remove Cu Kβ radiation, and an X'Celeratordetector. The instrument was calibrated by the vendor using a siliconpowder standard NIST #640c. The calibration was found to be correct whenit was tested with NIST #675 low-angle diffraction standard. The samplewas prepared for PXRD scanning by placing several milligrams of compoundonto a sample holder and smoothing as flat as possible by pressing weighpaper down on the sample with a flat object. The sample was analyzedusing a spinning-sample stage. Scans covered the range of 5 to 40° 2θ. Acontinuous scan mode was used with a step size of 0.0170° 2θ.Diffraction data were viewed and analyzed with the X'Pert Data ViewerSoftware, version 1.0a and X'Pert HighScore Software, version 1.0b.

The PXRD pattern for Form I of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea(Compound I) is shown in FIG. 21.

TABLE 33 Observed Peaks for Form I of 1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea (CompoundI) Ranging from 5 °2θ to 30 °2θ Pos. [°2θ] Rel. Int. [%] 5.6* 100.0 7.4*23.4 7.7 9.5 9.2 0.1 9.7 0.3 11.2* 25.7 11.6 7.6 12.8 4.9 12.8 4.9 14.02.8 14.5 1.4 15.2 4.3 15.5 3.5 15.7 5.5 16.1 2.2 16.5 1.5 17.9 1.9 18.55.1 19.3 3.2 20.3 3.5 20.4 4.4 21.1* 49.3 22.0 2.0 22.5 1.9 23.1 1.723.9 1.3 24.3 2.3 24.5 2.9 25.0* 17.4 25.6 4.2 26.0 4.8 26.3 5.8 26.89.5 26.9 8.3 27.4 4.0 28.0 8.1 28.1 7.9 28.8 4.8 29.1 3.9 *Peaks ofabout 17% or greater relative intensity.

The PXRD pattern for a tetrahydrofuran solvate of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea(Compound I) is shown in FIG. 29.

The PXRD pattern for a heptane solvate of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea(Compound I) is shown in FIG. 30.

Example 13: Differential Scanning Calorimetry for Form I of1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea(Compound I)

Differential Scanning Calorimetry (DSC) was performed on a TAinstruments, Inc. DSC Q2000 at 10° C./min. The instrument was calibratedat this scan rate by the vendor for temperature and energy using themelting point and enthalpy of fusion of an indium standard.

Samples were prepared by taring a sample-pan lid along with a sample-panbottom on a Mettler Toldeo MX5 balance. Sample was placed in the bottomof the tared sample pan. The sample-pan lid fitted snuggly in thesample-pan bottom. The sample and pan were reweighed to get the sampleweight. Thermal events (for example, onset temperature, enthalpy offusion) are calculated using the Universal Analysis 2000 software,version 4.1D, Build 4.1.0.16.

The DSC thermogram for Form I of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea(Compound I) is shown in FIG. 22.

Example 14: FT-Raman Spectroscopy for Form I of1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea(Compound I)

The Raman spectrum for Form I of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea(Compound I) was recorded using the ThermoFisher NXR6700 FT-RamanSpectrometer (EQ1874), NXR6700 FT-Raman Spectrometer (ThermoFisherScientific, Serial # AHR0700837), NXR FT-Raman Module (ThermoFisherScientific AEU0700442) and using the FT-Raman Micro-Stage Accessory(ThermoFisher Scientific AIS0800151). The instrument comprises a NdYAglaser operating at a wavelength of 1064 nm, an interferometer with acalcium fluoride beam-splitter, and an InGaAs detector. No backgroundspectrum was required, and the Raman spectra were recorded by placingapproximately 1 mg of each sample directly into the powder cup on thesample stage.

In order to collect the spectra, 1024 transients of an interferogramcontaining 8192 points were acquired with 4 cm⁻¹ resolution. Thespectrum was recorded from 100 cm⁻¹ to 3700 cm⁻¹. The interferogram wasapodized with a Happ-Genzel function and the data was zero-filled onceprior to the application of a power spectrum for phase correction.

Collection and Processing Information

Number of sample scans: 2048; Collection length: 4240.4 sec; Resolution:4.000; Levels of zero filling: 1; Number of scan points: 16672; Numberof FFT points: 32768; Laser frequency: 15798.3 cm⁻¹; Interferogram peakposition: 8192; Apodization: Happ-Genzel; Phase correction: Powerspectrum; Number of background scans: 0; and Background gain: 0.0.

Data Description:

Number of points: 3737, X-axis: Raman shift (cm-1), Y-axis: Ramanintensity, First X value: 99.2486, Last X value: 3701.6821, Raman laserfrequency: 9393.6416, Data spacing: 0.964249.

Spectrometer Description:

Spectrometer: Nicolet 6700, Source: Off, Detector: InGaAs, SmartAccessory ID: Unknown, Beamsplitter: CaF2, Sample spacing: 1.0000,Digitizer bits: 24, Mirror velocity: 0.3165, Aperture: 59.00, Samplegain: 64.0, High pass filter: 200.0000, Low pass filter: 11000.0000.

Data Processing:

Final format: Shifted spectrum, Resolution: 4.000 from 99.2486 to3701.6821, Laser power at sample: 0.699 W.

The FT-Raman Spectrum for Form I of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea(Compound I) is shown in FIG. 23.

Example 15: Thermogravimetric Analysis (TGA) for Form I of1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea(Compound I)

Thermal Gravimetric Analysis (TGA) was performed on the TA Instruments,Inc. TGA Q500. The instrument is calibrated by the vendor at 10° C./min.for temperature using the curie point of a ferromagnetic standard. Thebalance is calibrated with a standard weight. Sample scans are performedat 10° C./min. Sample was placed into an open sample pan, previouslytared on the TGA balance. Thermal events such as weight-loss arecalculated using the Universal Analysis 2000 software, version 4.1D,Build 4.1.0.16.

The TGA thermogram for Form I of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea(Compound I) is shown in FIG. 24.

Example 16: Single-Crystal X-Ray Structure of Hemi-Acetonitrile Solvateof1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea

Crystal structure determination was carried out under non-GMP conditionsat Purdue Crystallography Laboratory, West Lafayette, Ind.

1. Data Collection

A colorless needle of C₁₈H₁₅BrF₂N₄O₂, 0.5(CH₃CN) having approximatedimensions of 0.47×0.13×0.11 mm was mounted on a glass fiber in a randomorientation. Preliminary examination and data collection were performedMo K_(α) radiation (A=0.71073 A) on a Nonius KappaCCD equipped with agraphite crystal, incident beam monochromator.

Cell constants for data collection were obtained from least-squaresrefinement, using the setting angles of 17249 reflections in the range3<θ<25 0. The refined mosaicity from DENZO/SCALEPACK (Otwinowski et al.,Methods Enzymology 1997, 276, 307) was 0.51° indicating moderate crystalquality. The space group was determined by the program XPREP (Bruker,XPREP in SHELXTL version 6.12, Bruker AXS Inc., Madison, Wis., USA,(2002)). There were no systematic absences; the space group wasdetermined to be P-1 (no 2).

The data were collected at a temperature of 150° K. Data were collectedto a maximum 20 of 51.2°.

2. Data Reduction

A total of 17249 reflections were collected, of which 6818 were unique.Frames were integrated with DENZO-SMN (Otwinowski et al., MethodsEnzymology 1997, 276, 307).

Lorentz and polarization corrections were applied to the data. Thelinear absorption coefficient is 21.3/cm for Mo Kα radiation. Anempirical absorption correction using SCALEPACK (Otwinowski et al.,Methods Enzymology 1997, 276, 307) was applied. Transmissioncoefficients ranged from 0.688 to 0.791. Intensities of equivalentreflections were averaged. The agreement factor for the averaging was6.1% based on intensity.

3. Structure Solution and Refinement

The structure was solved by direct methods using SIR2004 (Burla et al.,J. Appl. Cryst., 2005, 38, 381). The remaining atoms were located insucceeding difference Fourier syntheses. Hydrogen atoms were included inthe refinement but restrained to ride on the atom to which they arebonded. The structure was refined in full-matrix least-squares byminimizing the function:

Σw(|F _(o) ² |−|F _(c)|²)²

The weight w is defined as:

1/[σ²(F _(o) ²)+(0.0600P)²+7.0096P] where P=(F _(o) ²+2F _(c) ²)/3

Scattering factors were taken from the “International Tables forCrystallography” (International Tables for Crystallography, Vol. C,Kluwer Academic Publishers, Utrecht, The Netherlands, (1992), Tables4.2.6.8 and 6.1.1.4.). Of the 6818 reflections were used in therefinements, only 5185 reflections with F_(o) ²>2σ (F_(o) ²) were usedin calculating R I. The final cycle of refinement included 575 variableparameters and converged (largest parameter shift was <0.01 times itsestimated standard deviation) with unweighted and weighted agreementfactors of:

R = ΣF_(o) − F_(c)/Σ F_(o) = 0.079$R_{w} = {\sqrt{\left( {\Sigma \; {{w\left( {F_{o}^{2} - F_{c}^{2}} \right)}^{2}/\Sigma}\; {w\left( F_{o}^{2} \right)}^{2}} \right)} = 0.161}$

The standard deviation of an observation of unit weight was 1.11. Thehighest peak in the final difference Fourier had a height of 0.62 e/A³.The minimum negative peak had a height of −1.07 e/A³.

Refinement was performed on a LINUX PC using SHELX-97 (Sheldrick,SHELXL97, A Program for Crystal Structure Refinement, Univ. ofGottingen, Germany, (1997)).

The crystallographic drawing in FIG. 25 was done using Mercury v. 1.4.2(build 2).

Example 17: Powder X-Ray Diffraction of Form II of1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea(Compound I)

Powder X-ray Diffraction (PXRD) data were collected on an X'Pert PRO MPDpowder diffractometer (PANalytical, Inc.) with a Cu source set at 45 kVand 40 mA, a Ni-filter to remove Cu Kβ radiation, and an X'Celeratordetector. The instrument was calibrated by the vendor using a siliconpowder standard NIST #640c. The calibration was found to be correct whenit was tested with NIST #675 low-angle diffraction standard. The samplewas prepared for PXRD scanning by placing several milligrams of compoundonto a sample holder and smoothing as flat as possible by pressing weighpaper down on the sample with a flat object. The sample was analyzedusing a spinning-sample stage. Scans covered the range of 5 to 40° 2θ. Acontinuous scan mode was used with a step size of 0.0170°2θ. Diffractiondata were viewed and analyzed with the X'Pert Data Viewer Software,version 1.0a and X'Pert HighScore Software, version 1.0b.

The PXRD pattern for Form II of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea(Compound I) is shown in FIG. 31.

TABLE 34 Observed Peaks for Form II of 1-[3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea (CompoundI) Ranging from 5 °2θ to 30 °2θ Pos.[°2θ] Rel. Int. [%] 5.3 0.4 5.9 0.36.8 0.2 8.2* 37.6 8.7 1.0 9.9 10.9 10.5 4.1 11.5* 18.6 12.3* 100.0 12.78.9 14.1 5.5 15.6 8.8 16.5 0.2 17.3 6.5 19.0 6.2 19.1 5.5 19.6 9.7 19.9*20.0 20.4* 16.2 21.1 3.3 22.0 4.7 22.1 5.0 23.0 8.9 24.6* 18.4 24.7*14.5 25.5 2.0 26.9 4.4 27.6 0.5 28.4 5.2 28.5 7.3 28.8 5.6 29.6 4.8 30.02.1 31.6 0.4 32.4 0.5 33.0 0.8 33.8 3.1 34.5 3.8 35.0 0.4 36.0 1.2 36.52.9 37.3 0.3 38.7 1.7 39.7 0.4 *Peaks of about 14% or greater relativeintensity.

Those skilled in the art will recognize that various modifications,additions, substitutions and variations to the illustrative examples setforth herein can be made without departing from the spirit of theinvention and are, therefore, considered within the scope of theinvention. All documents referenced above, including, but are notlimited to, printed publications and provisional and regular patentapplications, are incorporated herein by reference in their entirety.

What is claimed is: 1-50. (canceled)
 51. A process for preparing Form Iof1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureacomprising the step of: converting an acetonitrile solvate of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureato provide said Form I of1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureaby removing acetonitrile at a reduced pressure of about 100 mm Hg orless at a first temperature of about 0° C. to about 45° C. until theloss on drying is about 35%; and thereafter raising said firsttemperature to a second temperature of about 45° C. to about 90° C.,while maintaining said reduced pressure of about 100 mm Hg or less. 52.The process of claim 51 wherein said reduced pressure is about 10 mm Hgor less.
 53. The process of claim 51 wherein said reduced pressure isabout 5 mm Hg or less.
 54. A process for preparing1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureacomprising the step of reacting3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine with2,4-difluorophenyl isocyanate in the presence of acetonitrile; whereinthe reaction is conducted in the presence of 10% of H₂O or less; whereinthe temperature is about −30° C. to about 10° C.; wherein the resultantreaction mixture comprises less than about 1% of3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine with respectto1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureaas determined by HPLC.
 55. The process of claim 54 wherein the reactionis conducted in the presence of 1% of H₂O or less.
 56. The process ofclaim 54 wherein the reaction is conducted in the presence of 0.1% ofH₂O or less.
 57. The process of claim 54 wherein the temperature isabout −15° C. to about −5° C.
 58. The process of claim 54 wherein theresultant reaction mixture comprises less than about 0.1% of3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine with respectto1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureaas determined by HPLC.
 59. The process of claim 54 further comprisingthe crystallization of said1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-ureawherein the crystallization is conducted at a temperature of about −25°C. to about 5° C.
 60. The process of claim 59 wherein saidcrystallization is conducted at a temperature of about −10° C. to about−5° C.
 61. The process of claim 54 wherein said3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine is preparedby the step comprising reactingN-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-acetamide withan inorganic base in the presence of a mixture of xylenes andn-propanol; wherein the reaction is conducted at a temperature of about75° C. to reflux; wherein the reaction is conducted in the presence of4% or less of water; wherein the volume ratio of the mixture of xylenesand n-propanol is about 7:1 to about 1:1.
 62. The process of claim 61wherein the inorganic base is selected from lithium hydroxide orpotassium hydroxide.
 63. The process of claim 61 wherein the reaction isconducted at a temperature of about 100° C. to reflux.
 64. The processof claim 61 wherein the reaction is conducted at a temperature of about105° C. to reflux.
 65. The process of claim 61 wherein the reaction isconducted at a temperature of about 110° C. to reflux.
 66. The processof claim 61 wherein the reaction is conducted at a temperature of about112° C. to reflux.
 67. The process of claim 61 wherein the reaction isconducted in the presence of 2% or less of water.
 68. The process ofclaim 61 wherein the reaction is conducted in the presence of 1% or lessof water.
 69. The process of claim 61 wherein the reaction is conductedin the presence of 0.5% or less of water.
 70. The process of claim 61wherein the volume ratio of the mixture of xylenes and n-propanol isabout 6:1 to about 4:1.
 71. The process of claim 61 wherein saidN-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-acetamide isprepared by the step comprising reactingN-[4-methoxy-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-acetamide with abrominating agent in the presence of N,N-dimethylfromamide at atemperature of about 25° C. to about 100° C.; wherein the molar ratio ofbrominating agent toN-[4-methoxy-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-acetamide is about2:1.
 72. The process of claim 71 wherein said brominating agent isselected from the list consisting of Br₂,1,3-dibromo-5,5-dimethylhydantoin, and pyridinium tribromide.
 73. Theprocess of claim 71 wherein the molar ratio is about 1.9:1.
 74. Theprocess of claim 71 wherein the molar ratio is about 1.8:1.
 75. Theprocess of claim 71 wherein the molar ratio is about 1.7:1.
 76. Theprocess of claim 71 wherein the molar ratio is about 1.6:1.
 77. Theprocess of claim 71 wherein the molar ratio is about 1.5:1.
 78. Theprocess of claim 71 wherein the molar ratio is about 1.4:1.
 79. Theprocess of claim 71 wherein the molar ratio is about 1.3:1.
 80. Theprocess of claim 71 wherein the molar ratio is about 1.2:1.
 81. Theprocess of claim 71 wherein the molar ratio is about 1.1:1.
 82. Theprocess of claim 71 wherein the molar ratio is about 1:1.
 83. Theprocess of claim 71 wherein the temperature is about 25° C. to about 75°C.
 84. The process of claim 71 wherein the temperature is about 25° C.to about 65° C.